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WO2024196952A1 - Évaluation de sous-type de tumeur pour une thérapie anticancéreuse - Google Patents

Évaluation de sous-type de tumeur pour une thérapie anticancéreuse Download PDF

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Publication number
WO2024196952A1
WO2024196952A1 PCT/US2024/020580 US2024020580W WO2024196952A1 WO 2024196952 A1 WO2024196952 A1 WO 2024196952A1 US 2024020580 W US2024020580 W US 2024020580W WO 2024196952 A1 WO2024196952 A1 WO 2024196952A1
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Prior art keywords
tumor
antibody
aspects
antagonist
subject
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PCT/US2024/020580
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English (en)
Inventor
William J. Geese
Robin H. EDWARDS
Dimple M. PANDYA
Vipul Atulkumar BAXI
David Edward BALLI
Original Assignee
Bristol-Myers Squibb Company
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Publication of WO2024196952A1 publication Critical patent/WO2024196952A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure provides methods of selecting a human subject suitable for anti-cancer therapy or anti-cancer therapies (e.g., immunotherapy or chemotherapy) based on a tumor histological subtype.
  • anti-cancer therapy or anti-cancer therapies e.g., immunotherapy or chemotherapy
  • checkpoint inhibitors have shown long-term benefits in 40% of melanoma patients, 80% of Hodgkin’s lymphoma patients, and 50% of Merkel cell carcinoma patients. (Schmidt C. The benefits of immunotherapy combinations. Nature 2017;552:S67-9).
  • the present disclosure is directed to a method of identifying a human subject afflicted with a tumor of a non-small cell lung cancer suitable for treatment with an immunotherapy, comprising assessing a tumor histologic subtype (THS) of the tumor, wherein the THS is solid.
  • the method further comprises administering an immunotherapy to the subject.
  • the present disclosure is directed to a method of treating a human subject afflicted with a tumor of a non-small cell lung cancer of nonsquamous subtype, comprising administering an immunotherapy in the subject, wherein the subject is identified as having a solid tumor histologic subtype (THS).
  • TLS solid tumor histologic subtype
  • the present disclosure is directed to a method of identifying a population of human subjects, each subject afflicted with a tumor of a nonsquamous non-small cell lung cancer suitable for treatment with an immunotherapy, wherein each subject is identified as having a solid tumor histological subtype (THS).
  • TLS solid tumor histological subtype
  • the disclosure provides a method of selecting a treatment for a human subject afflicted with a tumor of a nonsquamous non-small cell lung cancer, the method comprising
  • TLS tumor histological subtype
  • the selecting comprises choosing a treatment that comprises an immunotherapy for the subject; or (ii) if the THS is ascinar, the selecting comprises choosing a treatment that comprises a chemotherapy and/or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors for the subject.
  • the method further comprises administering an immunotherapy to the subject having a tumor with a solid THS. In some aspects, the method further comprises administering an immunotheray to the subject having a tumor with a solid THS.
  • the method further comprises administering a chemotherapy and/or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors to the subject having a tumor with an ascinar THS.
  • the method comprises administering a chemotherapy to the subject, optionally in combination with an agent that acts to inhibit a pathway that is upregulated in ascinar tumors.
  • the method comprises administering an agent that acts to inhibit a pathway that is upregulated in ascinar tumors to the subject (e.g., an agent that inhibits angiogenesis and/or an agent that inhibits one or more of TGFb, KRAS, hedgehog, and notch signalling pathways).
  • the method does not comprise administering an immunotherapy to the subject having a tumor with an ascinar THS.
  • the method further comprises administering an immunotherapy to the subject having a tumor with an ascinar THS.
  • the present disclosure provides a method of identifying a human subject afflicted with a tumor of a nonsquamous non-small cell lung cancer suitable for treatment with a chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors, the method comprising assessing a tumor histologic subtype (THS) of the tumor from the subject, wherein the THS is ascinar.
  • the method further comprises administering a chemotherapy and/or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors (e.g., an agent that inhibits angiogenesis and/or an agent that inhibits one or more of TGFb , KRAS, hedgehog, and notch signalling pathways) to the subject.
  • the method comprises administering a chemotherapy to the subject.
  • the method does not comprise administering an immunotherapy to the subject.
  • the method further comprises administering an immunotherapy to the subject.
  • the present disclosure provides a method of treating a human subject afflicted with a tumor of a nonsquamous non-small cell lung cancer comprising administering a chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors to the subj ect, wherein the subj ect is identified as having an ascinar tumor histologic subtype (THS).
  • a chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors to the subj ect, wherein the subj ect is identified as having an ascinar tumor histologic subtype (THS).
  • THS tumor histologic subtype
  • the present disclosure provides a method of treating a population of human subjects with a chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors, wherein each subject is afflicted with a tumor of a non-small cell lung cancer, wherein each subject is identified as having an ascinar tumor histological subtype (THS).
  • TLS tumor histological subtype
  • the present disclosure provides a method of identifying a population of human subjects suitable for treatment with a chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors, each subject afflicted with a tumor of a nonsquamous non-small cell lung cancer, wherein each subject is identified as having a ascinar tumor histological subtype (THS).
  • the chemotherapy useful for the present disclosure comprises gemcitabine, cisplatin, carboplatin, premetrexed, paclitaxel, or any combination thereof.
  • the tumor expresses at least 1% membraneous PD-L1.
  • the methods of the disclosure further comprise measuring a PD-L1 expression in the tumor.
  • PD-L1 expression in the tumor is measured by a Dx 28-8 assay or a similar panelbased assay.
  • the tumor has a high tumor mutational burden (TMB).
  • the methods of the disclosure further comprise measuring a TMB in the tumor.
  • the TMB in the tumor is measured by a FMI CDx assay or a similar panel-based assay, e.g., TS0500.
  • the tumor has an inflammatory gene signature.
  • the methods of the disclosure further comprise measuring an inflammatory gene signature in the tumor.
  • the inflammatory gene signature in the tumor is measured by an RNA- Seq.
  • the nonsquamous non-small cell lung cancer is an Occult (hidden) NSCLC, a stage 0 NSCLC, a stage IA1 NSCLC, a stage IA2 NSCLC, a stage IA3 NSCLC, a stage IB NSCLC, a stage IIA NSCLC, a stage IIB NSCLC, a stage IIIA NSCLC, a stage IIIB NSCLC, a stage IIIC NSCLC, a stage IVA NSCLC, or a stage IVB NSCLC.
  • Occult hidden
  • the nonsquamous non-small cell lung cancer is a nonmetastatic NSCLC.
  • the nonsquamous non-small cell lung cancer is a metastatic NSCLC.
  • the methods of the disclosure further comprise assessing the stage of the NSCLC.
  • the stage of the NSCLC in accordance with a TNM cancer staging system.
  • the immunotherapy comprises a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, a LAG-3 antagonist, a TIM3 antagonist, a TIGIT antagonist, a TIM3 antagonist, a NKG2a antagonist, an 0X40 antagonist, an ICOS antagonist, a MICA antagonist, a CD 137 antagonist, a KIR antagonist, a TGFP antagonist, an IL- 10 antagonist, an IL- 8 antagonist, a B7-H4 antagonist, a Fas ligand antagonist, a CXCR4 antagonist, a mesothelin antagonist, a CD27 antagonist, a GITR antagonist, or any combination thereof.
  • the immunotherapy comprises a small molecule.
  • the immunotherapy comprises a PD-1 antagonist.
  • the immunotherapy comprises anti-PD-1 antibody.
  • the anti-PD-1 antibody comprises an antibody comprising nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IB 1308, or any combination thereof.
  • the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1.
  • the anti-PD-1 antibody comprises nivolumab. In some aspects, the anti-PD-1 antibody cross-competes with pembrolizumab for binding to human PD-1. In some aspects, the anti-PD-1 antibody comprises pembrolizumab. In some aspects, the immunotherapy comprises a PD-L1 antagonist. In some aspects, the PD-L1 antagonist comprises an anti-PD-Ll antibody. In some aspects, the anti-PD-Ll antibody comprises an antibody comprising BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301, ICO 36, or any combination thereof.
  • the anti-PD-Ll antibody cross-competes with atezolizumab for binding to human PD-L1. In some aspects, the anti-PD-Ll antibody comprises atezolizumab. In some aspects, the anti-PD-Ll antibody cross-competes with durvalumab for binding to human PD-L1. In some aspects, the anti- PD-Ll antibody comprises durvalumab. In some aspects, the anti-PD-Ll antibody cross-competes with avelumab for binding to human PD-L1. In some aspects, the anti-PD-Ll antibody comprises avelumab. In some aspects, the anti-PD-Ll comprises BMS-986189.
  • the immunotherapy comprises a combination of (i) an anti-PD-1 antibody or an anti-PD-Ll antibody and (ii) a second agent.
  • the second agent comprises a second antibody.
  • the second antibody comprises a CTLA-4 antagonist, a LAG-3 antagonist, a TIM3 antagonist, a TIGIT antagonist, a TIM3 antagonist, a NKG2a antagonist, an 0X40 antagonist, an ICOS antagonist, a MICA antagonist, a CD 137 antagonist, a KIR antagonist, a TGFP antagonist, an IL-10 antagonist, an IL-8 antagonist, a B7-H4 antagonist, a Fas ligand antagonist, a CXCR4 antagonist, a mesothelin antagonist, a CD27 antagonist, a GITR antagonist, or any combination thereof.
  • the second antibody comprises an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti- TIGIT antibody, an anti-TIM3 antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti- ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti- TGFP antibody, an anti -IL- 10 antibody, an anti-IL-8 antibody, an anti-B7-H4 antibody, an anti- Fas ligand antibody, an anti-CXCR4 antibody, an anti -mesothelin antibody, an anti-CD27 antibody, an anti-GITR, or any combination thereof.
  • the second antibody comprises an anti-CTLA-4 antibody.
  • the immunotherapy comprises an anti-PD- 1 antibody and an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody crosscompetes with ipilimumab for binding to human CTLA-4.
  • the anti-CTLA-4 antibody comprises ipilimumab.
  • the anti-CTLA-4 antibody cross-competes with tremelimumab for binding to human CTLA-4.
  • the anti-CTLA-4 antibody comprises tremelimumab.
  • the second agent comprises a LAG-3 antagonist.
  • the LAG-3 antagonist comprises an anti-LAG-3 antibody.
  • the immunotherapy comprises an anti-PD-1 antibody and an anti-LAG-3 antibody.
  • the LAG-3 antagonist is a soluble LAG-3 polypeptide.
  • the soluble LAG-3 polypeptide is a fusion polypeptide.
  • the soluble LAG-3 polypeptide comprises a ligand binding fragment of the LAG-3 extracellular domain.
  • the soluble LAG-3 polypeptide further comprises a half-life extending moiety.
  • half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin- binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof.
  • the soluble LAG-3 polypeptide is IMP321 (eftilagimod alpha).
  • the anti-LAG-3 antibody cross-competes with BMS-986016 (relatlimab) for binding to human LAG-3.
  • the anti-LAG-3 antibody comprises BMS-986016 (relatlimab).
  • the anti-LAG-3 antibody comprises BMS-986016 (relatlimab), LAG-525 (IMP-701, ieramilimab), MK-4280 (28G-10), REGN3767 (fianlimab), TSR-033, TSR- 075, Sym022, FS-118, IMP731 (H5L7BW), GSK2831781, humanized BAP050, aLAG3(0414), aLAG3(0416), XmAb22841, MGD013, BI754111, P 13B02-30, AVA-017, 25F7, AGEN1746, or comprises an antigen binding portion thereof.
  • the immunotherapy comprises nivolumab and ipilimumab. In some aspects, the immunotherapy comprises nivolumab and relatlimab.
  • the immunotherapy is administered at a flat dose. In some aspects, the immunotherapy is administered at a weight-based dose.
  • the THS is obtained from a tumor sample from the subject.
  • the tumor sample comprises one or more tumor sections derived from a tumor tissue biopsy or a tumor tissue resection.
  • the one or more tumor sections comprise a formalin- fixed, paraffin-embedded tumor tissue or a fresh-frozen tumor tissue.
  • the one or more tumor sections comprise serially sectioned tumor sections.
  • the one or more tumor sections are stained by immunohistochemistry (IHC).
  • IHC immunohistochemistry
  • the one or more tumor sections comprise one tumor section, two tumor sections, three tumor sections, four tumor sections, five tumor sections, six tumor sections, seven tumor sections, eight tumor sections, nine tumor sections, ten tumor sections, 11 tumor sections, 12 tumor sections, 13 tumor sections, 14 tumor sections, 15 tumor sections, 16 tumor sections, 17 tumor sections, 18 tumor sections, 19 tumor sections, 20 tumor sections, 21 tumor sections, 22 tumor sections, 23 tumor sections, 24 tumor sections, 25 tumor sections, 26 tumor sections, 27 tumor sections, 28 tumor sections, 29 tumor sections, or 30 tumor sections.
  • the first tumor section, the second tumor section, and the third tumor section are serially sectioned from the tumor sample.
  • the immunotherapy dose is administered once about every one week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, or once about every twelve weeks.
  • the methods of the disclosure further comprise administering to the subject an additional therapeutic agent.
  • the additional therapeutic agent comprises an anti-cancer agent.
  • the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.
  • the tyrosine kinase inhibitor comprises sorafenib, lenvatinib, regorafenib, cabozantinib, sunitinib, brivanib, linifanib, erlotinib, pemigatinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, temsirolimus, or any combination thereof.
  • the anti-angiogenesis agent comprises an inhibitor of a vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase with Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c- MET), C-type lectin family 14 member A (CLEC14A), multimerin 2 (MMRN2), shock protein 70-1A (HSP70-1A), a epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof.
  • VEGF vascular endothelial growth factor
  • VGF VEGF receptor
  • PDGF platelet-derived growth factor
  • PDGFR PDGF receptor
  • Ang angiopoietin
  • Ang tyrosine kinase with Ig
  • the anti-angiogenesis agent comprises bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesvacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.
  • the additional therapeutic agent is administered in combination with the immunotherapy, the chemotherapy, or the agent that acts to inhibit a pathway that is upregulated in ascinar tumors.
  • the agent that acts to inhibit a pathway that is upregulated in ascinar tumors comprises a therapeutic agent that inhibits one or more of TGFb, KRAS, hedgehog, and notch signalling pathways.
  • the agent that acts to inhibit a pathway that is upregulated in ascinar tumors comprises an agent that inhibits angiogenesis.
  • the agent that inhibits angiogenesis comprises an agent than inhibits a VEGF receptor.
  • the agent that inhibits angiogenesis comprises bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesvacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.
  • a treatment selected and/or administered according to the methods herein reduces the size of a tumor associated with the cancer.
  • the size of the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors.
  • the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors.
  • the subject exhibits stable disease after the immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors.
  • the subject exhibits a partial response after the immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors. In some aspects, the subject exhibits a complete response after the immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors. In some aspects, the subject is not administered with a chemotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors.
  • Figs. 1A-1G show Kaplan Meier curves ploted for overall survival (Probability of OS) or progression-free survival (Probability of PFS) and stratified by tumor histologic subtype (Acinar, Solid), for Study I Part 1 (Figs. 1A-1B, Nivolumab+Ipilimumab 1A, and Chemotherapy IB), Study II (Fig. 1C, Nivolumab+Ipilimumab), Study III (Fig. 1D-1E, Nivolumab ID, and Chemotherapy IE), and Study IV (Figs. 1F-1G, Nivolumab+Ipilimumab+Chemotherapy IF, and Chemotherapy 1G).
  • HR (95% CI) indicates the Hazard Ratio (HR) and 95% Confidence Interval (CI) of the HR for each treatment, calculated for each tumor histologic subtype within each respective arm.
  • Figs. 2A-2D show tumor-based biomarker levels in acinar and solid tumors from Study I.
  • Fig. 2A shows a boxplot distribution of PD-L1 tumor proportion score (TPS) by tumor histologic subtype (acinar and solid).
  • Fig. 2B shows a boxplot distribution of tumor mutational burden (TMB) by tumor histologic subtype (acinar and solid).
  • TPS tumor histologic subtype
  • TMS tumor mutational burden
  • Fig. 2C shows differential gene expression (DGE) between acinar and solid tumors.
  • Fig. 2D shows a hallmark gene set enrichment by tumor histologic subtype (acinar and solid) DETAILED DESCRIPTION OF THE DISCLOSURE
  • the present disclosure provides a method of identifying a human subject afflicted with a tumor suitable for an anti-cancer therapy (e.g., immunotherapy and/or chemotherapy) comprising assessing the tumor histologic subtype (THS). In some aspects, the method further comprises administering an anti-cancer therapy (e.g., immunotherapy and/or chemotherapy) to the subject.
  • an anti-cancer therapy e.g., immunotherapy and/or chemotherapy
  • the present disclosure also provides a method of treating a human subject afflicted with a tumor identified as having a certain THS, comprising administering an anti-cancer therapy (e.g., immunotherapy and/or chemotherapy) to the subject.
  • the present disclosures demonstrate utility of tumor histologic subtype, as assessed from H&E-stained slides, as a biomarker of anti-cancer therapy (e.g., immunotherapy and/or chemotherapy) efficacy.
  • anti-cancer therapy e.g., immunotherapy and/or chemotherapy
  • Immunotherapy-based regimens were found to be more efficacious in solid tumor than acinar tumor.
  • Therapies containing chemotherapy were found to be more efficacious in acinar tumor than solid tumor.
  • Tumor histologic subtype assessment is an elegant approach to identify patients that have improved or reduced response to an anti-cancer therapy (e.g., immunotherapy and/or chemotherapy), based on a single H&E slide that is typically available for most NSCLC patients at the time of diagnosis.
  • Assessment of tumor histologic subtype captures the pathological features of the tumor microenvironment and also is shown herein to be associated with multiple other biological features that may be associated with response to an anti-cancer therapy (e.g., immunotherapy and/or chemotherapy).
  • tumor histologic subtype e.g., solid versus ascinar
  • PD-L1 tumor histologic subtype
  • TMB tumor histologic subtype
  • inflammation in nonsquamous NSCLC
  • This information can inform treatment decisions and outcomes expectations.
  • a or “an” entity refers to one or more of that entity; for example, “a nucleotide sequence,” is understood to represent one or more nucleotide sequences.
  • the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.
  • the terms “about” or “comprising essentially of’ refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, z.e., the limitations of the measurement system.
  • “about” or “comprising essentially of’ can mean within 1 or more than 1 standard deviation per the practice in the art.
  • “about” or “comprising essentially of’ can mean a range of up to 10% or 20% (z.e., ⁇ 10% or ⁇ 20%).
  • about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
  • the terms can mean up to an order of magnitude or up to 5-fold of a value.
  • the meaning of “about” or “comprising essentially of’ should be assumed to be within an acceptable error range for that particular value or composition.
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • fractions thereof such as one tenth and one hundredth of an integer
  • an “antagonist” shall include, without limitation, any molecule capable of blocking, reducing, or otherwise limiting an interaction or activity of a target molecule (e.g., PD-1).
  • the antagonist is an antibody.
  • the antagonist comprises a small molecule.
  • the terms “antagonist” and “inhibitor” are used interchangeably herein.
  • an “antibody” shall include, without limitation, a glycoprotein immunoglobulin which binds specifically to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding portion thereof.
  • Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region comprises three constant domains, CHI, CH2 and CHS.
  • Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprises one constant domain, CL.
  • the NH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • Each NH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • a heavy chain can have the C-terminal lysine or not.
  • An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4.
  • Isotype refers to the antibody class or subclass (e.g., IgM or IgGl) that is encoded by the heavy chain constant region genes.
  • antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or nonhuman antibodies; wholly synthetic antibodies; single chain antibodies; monospecific antibodies; bispecific antibodies; and multi-specific antibodies.
  • a nonhuman antibody can be humanized by recombinant methods to reduce its immunogenicity in man.
  • the term “antibody” also includes an antigen-binding fragment or an antigen-binding portion of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, that retains the ability to bind specifically to the antigen bound by the whole immunoglobulin.
  • an “antigen-binding portion” or “antigen-binding fragment” include: (1) a Fab fragment (fragment from papain cleavage) or a similar monovalent fragment consisting of the VL, VH, LC and CHI domains; (2) a F(ab’)2 fragment (fragment from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (3) a Fd fragment consisting of the VH and CHI domains; (4) a Fv fragment consisting of the VL and VH domains of a single arm; (5) a single domain antibody (dAb) fragment (Ward et al., (1989) Nature 341 :544-546), which consists of a VH domain; (6) a bi-single domain antibody which consists of two VH domains linked by a hinge (dual-affinity re-targeting antibodies (DARTs)); or (7) a dual variable domain immunoglobul
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., w etal. (1988) Science 242:423-426; and Huston etal. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • scFv single chain Fv
  • antigen-binding portions or fragments are obtained using conventional techniques known to those with skill in the art, and the portions or fragments are screened for utility in the same manner as are intact antibodies.
  • Antigen-binding portions or fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.
  • An “isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that binds specifically to PD-1 is substantially free of antibodies that bind specifically to antigens other than PD-1).
  • An isolated antibody that binds specifically to PD-1 may, however, have cross-reactivity to other antigens, such as PD-1 molecules from different species.
  • an isolated antibody can be substantially free of other cellular material and/or chemicals.
  • mAb refers to a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules whose primary sequences are essentially identical, and which exhibits a single binding specificity and affinity for a particular epitope.
  • a monoclonal antibody is an example of an isolated antibody.
  • Monoclonal antibodies can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • a “human antibody” refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the human antibodies of the disclosure can include amino acid residues not encoded by human germline immunoglobulin sequences e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term “human antibody,” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • a “humanized antibody” refers to an antibody in which some, most or all of the amino acids outside the CDRs of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one aspect of a humanized form of an antibody, some, most or all of the amino acids outside the CDRs have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDRs are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen.
  • a “humanized antibody” retains an antigenic specificity similar to that of the original antibody.
  • a “chimeric antibody” refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
  • an “anti-antigen antibody” refers to an antibody that binds specifically to the antigen.
  • an anti-PD-1 antibody binds specifically to PD-1
  • an anti-PD-Ll antibody binds specifically to PD-L1
  • an anti -LAG-3 antibody binds specifically to LAG-3
  • an anti- CTLA-4 antibody binds specifically to CTLA-4.
  • PD-1 Programmed Death-1
  • PD-1 refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2.
  • the term “PD-1” as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank Accession No. U64863. “PD-1” and “PD-1 receptor” are used interchangeably herein.
  • P-L1 Programmed Death Ligand-1
  • PD-L1 is one of two cell surface glycoprotein ligands for PD- 1 (the other being PD-L2) that downregulate T cell activation and cytokine secretion upon binding to PD-1.
  • the term “PD-L1” as used herein includes human PD-L1 (hPD-Ll), variants, isoforms, and species homologs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll.
  • the complete hPD-Ll sequence can be found under GenBank Accession No. Q9NZQ7.
  • the human PD-L1 protein is encoded by the human CD274 gene (NCBI Gene ID: 29126).
  • the terms “Programmed Death Ligand-2” and “PD-L2” as used herein include human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs having at least one common epitope with hPD-L2.
  • the complete hPD-L2 sequence can be found under GenBank Accession No. Q9BQ51.
  • LAG-3 refers to Lymphocyte Activation Gene-3.
  • the term “LAG-3” includes variants, isoforms, homologs, orthologs and paralogs.
  • antibodies specific for a human LAG-3 protein can, in certain cases, cross-react with a LAG-3 protein from a species other than human.
  • the antibodies specific for a human LAG-3 protein can be completely specific for the human LAG-3 protein and not exhibit species or other types of cross-reactivity, or can cross-react with LAG-3 from certain other species, but not all other species (e.g., cross-react with monkey LAG-3 but not mouse LAG-3).
  • human LAG-3 refers to human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 having GenBank Accession No. NP_002277.
  • mouse LAG-3 refers to mouse sequence LAG-3, such as the complete amino acid sequence of mouse LAG-3 having GenBank Accession No. NP 032505.
  • LAG-3 is also known in the art as, for example, CD223.
  • the human LAG-3 sequence can differ from human LAG-3 of GenBank Accession No. NP_002277 by having, e.g., conserved mutations or mutations in non-conserved regions, and the LAG-3 has substantially the same biological function as the human LAG-3 of GenBank Accession No. NP 002277.
  • a biological function of human LAG-3 is having an epitope in the extracellular domain of LAG-3 that is specifically bound by an antibody of the instant disclosure or a biological function of human LAG-3 is binding to MHC Class II molecules.
  • CTLA-4 Cytotoxic T-Lymphocyte Antigen-4
  • CD80 and CD86 also called B7-1 and B7-2, respectively.
  • CTLA- 4 as used herein includes human CTLA-4 (hCTLA-4), variants, isoforms, and species homologs of hCTLA-4, and analogs having at least one common epitope with hCTLA-4.
  • the complete hCTLA-4 sequence can be found under GenBank Accession No. AAB59385.
  • T cell Immunoglobulin and Mucin domain-3 (TIM-3), also known as hepatitis A virus cellular receptor 2 (HAVCR2), refers to a type-I transmembrane protein that was initially identified on activated IFN-y producing T cells (e.g., type 1 helper CD4+ T cells and cytotoxic CD8+ T cells) and shown to induce T cell death or exhaustion after binding to galectin-9.
  • TIM-3 as used herein includes human TIM-3 (hTIM-3), variants, isoforms, and species homologs of hTIM-3, and analogs having at least one common epitope with hTIM-3. Two isoforms of hTIM-3 have been identified. Isoform 1 (GenBank Accession No. NP_116171) consists of 301 amino acids and represents the canonical sequence. Isoform 2 (GenBank Accession No. AAH20843) consists of 142 amino acids, and is soluble.
  • PD-L1 positive or “PD-L1 expression positive,” relating to cell surface PD-L1 expression, refers to the proportion of cells in a test tissue sample comprising tumor cells and tumor-infiltrating inflammatory cells above which the sample is scored as expressing cell surface PD-L1.
  • PD-L 1 negative or “PD-L 1 expression negative,” relating to cell surface PD-L1 expression, refers to the proportion of cells in a test tissue sample comprising tumor cells and tumor- infiltrating inflammatory cells that are not PD-L1 positive or PD-L1 expression positive.
  • chemotherapeutic agent refers to a chemical substance that can cause death of cancer cells, or interfere with growth, division, repair, and/or function of cancer cells.
  • Classes of chemotherapeutic agents include but are not limited to: alkylating agents (including nitrosoureas), antimetabolites, antitumor antibiotics, topisomerase inhibitors (e.g., plant alkaloids), mitotic inhibitors (e.g., plant alkaloids), corticosteroids (or steroids), and others.
  • TMB tumor mutation burden
  • IMS Tumor Inflammation Signature
  • gene transcripts associated with the presence of an immune response e.g., genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance.
  • Gene expression in the tumor microenvironment maybe assessed by various technology platforms, and different, but highly correlated, gene transcripts.
  • a “subject” includes any human or nonhuman animal.
  • the term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In preferred aspects, the subject is a human.
  • the terms, “subject” and “patient” are used interchangeably herein.
  • administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • Preferred routes of administration for the anti-cancer therapy include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, as well as in vivo electroporation.
  • the formulation is administered via a non-parenteral route, in some aspects, orally.
  • non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • Treatment or “therapy” of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease.
  • Response Evaluation Criteria In Solid Tumors is a measure for treatment efficacy and are established rules that define when tumors respond, stabilize, or progress during treatment.
  • RECIST 1.1 is the current guideline to solid tumor measurement and definitions for objective assessment of change in tumor size for use in adult and pediatric cancer clinical trials.
  • effective treatment refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder.
  • a beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method.
  • a beneficial effect can also take the form of arresting, slowing, retarding, or stabilizing of a deleterious progression of a marker of solid tumor.
  • Effective treatment can refer to alleviation of at least one symptom of a solid tumor.
  • Such effective treatment can, e.g., reduce patient pain, reduce the size and/or number of lesions, can reduce or prevent metastasis of a tumor, and/or can slow tumor growth.
  • an effective amount refers to an amount of an agent that provides the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to prevent or delay tumor recurrence.
  • An effective amount can be administered in one or more administrations.
  • the effective amount of the drug or composition can: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and can stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and can stop tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • an “effective amount” is the amount of anti-LAG-3 antibody alone or the amount of anti- LAG-3 antibody and the amount an additional therapeutic agent (e.g., anti-PD-1 antibody), in combination, clinically proven to affect a significant decrease in cancer or slowing of progression of cancer, such as an advanced solid tumor.
  • an additional therapeutic agent e.g., anti-PD-1 antibody
  • the terms “fixed dose”, “flat dose” and “flat-fixed dose” are used interchangeably and refer to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient.
  • the fixed or flat dose is therefore not provided as a mg/kg dose, but rather as an absolute amount of the agent (e.g., an amount in pg or mg).
  • fixed dose combination with regard to a composition of the invention means that two or more different inhibitors as described herein (e.g., an anti-LAG-3 antibody and an anti-PD-1 antibody) in a single composition are present in the composition in particular (fixed) ratios with each other.
  • the fixed dose is based on the weight (e.g., mg) of the inhibitors.
  • the fixed dose is based on the concentration (e.g., mg/ml) of the inhibitors.
  • the ratio is at least about 1:1, about 1 :2, about 1 :3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1 mg first inhibitor to mg second inhibitor.
  • the 3 : 1 ratio of a first antibody and a second antibody can mean that a vial can contain about 240 mg of the first antibody and 80 mg of the second antibody or about 3 mg/ml of the first antibody and 1 mg/ml of the second antibody.
  • weight based dose means that a dose that is administered to a patient is calculated based on the weight of the patient. For example, when a patient with 60 kg body weight requires 3 mg/kg of an anti-LAG-3 antibody in combination with 3 mg/kg of an anti-PD-1 antibody, one can draw the appropriate amounts of the anti-LAG-3 antibody (z.e., 180 mg) and the anti-PD-1 antibody (z.e., 180 mg) at once from a 1:1 ratio fixed dose combination of an anti-LAG3 antibody and an anti-PD-1 antibody.
  • Dosing interval means the amount of time that elapses between multiple doses of a formulation disclosed herein being administered to a subject. Dosing interval can thus be indicated as ranges.
  • Dosing frequency refers to the frequency of administering doses of a formulation disclosed herein in a given time. Dosing frequency can be indicated as the number of doses per a given time, e.g., once a week or once in two weeks, etc.
  • the terms “about once a week,” “once about every week,” “once about every two weeks,” or any other similar dosing interval terms as used herein means approximate number, and “about once a week” or “once about every week” can include every seven days ⁇ two days, i.e., every five days to every nine days.
  • the dosing frequency of “once a week” thus can be every five days, every six days, every seven days, every eight days, or every nine days.
  • “Once about every three weeks” can include every 21 days ⁇ 3 days, i.e., every 25 days to every 31 days.
  • a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose can be administered any day in the first week, and then the next dose can be administered any day in the sixth or twelfth week, respectively.
  • a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose is administered on a particular day of the first week (e.g., Monday) and then the next dose is administered on the same day of the sixth or twelfth weeks (i.e., Monday), respectively.
  • An “adverse event” as used herein is any unfavorable and generally unintended or undesirable sign (including an abnormal laboratory finding), symptom, or disease associated with the use of a medical treatment.
  • an adverse event can be associated with activation of the immune system or expansion of immune system cells (e.g., T cells) in response to a treatment.
  • a medical treatment can have one or more associated Aes and each AE can have the same or different level of severity.
  • Reference to methods capable of “altering adverse events” means a treatment regime that decreases the incidence and/or severity of one or more Aes associated with the use of a different treatment regime.
  • the term “tumor” as used herein refers to any mass of tissue that results from excessive cell growth or proliferation, either benign (non-cancerous) or malignant (cancerous), including pre-cancerous lesions.
  • an “anti-cancer agent” promotes cancer regression in a subject.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer.
  • “Promoting cancer regression” means that administering an effective amount of the anti-cancer agent, alone or in combination with another agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient.
  • Physiological safety refers to safety as determined based on the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the agent.
  • a therapeutically effective amount of an anti-cancer agent inhibits cell growth or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to untreated subjects.
  • tumor regression can be observed and continue for a period of at least about 20 days, at least about 40 days, or at least about 60 days.
  • evaluation of anti-cancer (e.g., immunotherapeutic or chemotherapeutic) drugs must also make allowance for immune-related response patterns.
  • an “immunotherapy”, “immune-oncology therapy”, an “I-O”, or “IO” therapy refers to a therapy that comprises utilizing an immune response to target and treat a tumor in a subject.
  • an 1-0 therapy is a type of anti-cancer therapy.
  • 1-0 therapy comprises administering an antibody or an antigen-binding fragment thereof to a subject.
  • an 1-0 therapy comprises administering to a subject an immune cell, e.g., a T cell, e.g., a modified T cell, e.g., a T cell modified to express a chimeric antigen receptor or a particular T cell receptor.
  • the 1-0 therapy comprises administering a therapeutic vaccine to a subject. In some aspects, the 1-0 therapy comprises administering a cytokine or a chemokine to a subject. In some aspects, the 1-0 therapy comprises administering an interleukin to a subject. In some aspects, the 1-0 therapy comprises administering an interferon to a subject. In some aspects, the 1-0 therapy comprises administering a colony stimulating factor to a subject.
  • an “immune response” refers to the action of a cell of the immune system (for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules produced by any of these cells or the liver (including antibodies, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and/or elimination from a vertebrate’s body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • a cell of the immune system for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils
  • soluble macromolecules produced by any of these cells or the liver including antibodies, cytokines, and complement
  • a “tumor-infiltrating inflammatory cell” or “tumor-associated inflammatory cell” is any type of cell that typically participates in an inflammatory response in a subject and which infiltrates tumor tissue. Such cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes and dendritic cells.
  • TILs tumor-infiltrating lymphocytes
  • macrophages macrophages
  • monocytes eosinophils
  • histiocytes histiocytes and dendritic cells.
  • tumor sample refers to tumor material isolated from a tumor of a subject.
  • the tumor sample can contain any portion of a tumor suitable for determining the tumor histologic subtype (THS), for example by staining the sample with Hematoxylin and Eosin (H&E) and/or immunohistochemistry (IHC).
  • TLS tumor histologic subtype
  • H&E Hematoxylin and Eosin
  • IHC immunohistochemistry
  • the tumor sample can also be suitable for determining target protein expression (e.g., PD-L1), by, for example, immunohistochemistry (IHC); measuring the tumor mutational burden (TMB) by, for example, a FMI CDx assay; and/or assessing the tumor inflammatory gene signature by, for example, RNA-Seq.
  • the tumor sample is a tumor tissue biopsy or a tumor tissue resection.
  • the tumor sample can be, for example, formalin-fixed, paraffin-embedded (FFPE) tumor tissue or a fresh-frozen tumor tissue or can be tumor tissue processed by any mean known in the art that is suitable for performing the desired assays (e.g., H&E staining, IHC, RNA-Seq and the like).
  • FFPE formalin-fixed, paraffin-embedded
  • the tumor sample can be sectioned into multiple tumor sections.
  • the tumor sample is serially sectioned into multiple sections.
  • the Kaplan Meier estimator or “product limit estimator,” refer to a non-parametric statistic used to estimate the survival function from lifetime data.
  • the visual representation of this function is usually called the “Kaplan Meier curve,” and it shows what the probability of an event (for example, survival) is at a certain time interval.
  • Hazard Ratio refers to the ratio of the hazard rates corresponding to the conditions characterized by two distinct treatment variables of interest. For example, in a clinical study a population characterized by condition A may die at twice the rate per unit time of a population characterized by condition B. The hazard ratio would be 2, indicating higher hazard of death of the population characterized by feature A.
  • ITT population refers to all patients who were enrolled and randomly allocated to treatment.
  • ITT analysis refers to an analysis in which all patients who were enrolled and randomly allocated to treatment are included in the analysis and are analyzed in the groups to which they were randomized.
  • a human subject afflicted with a tumor suitable for an anti-cancer therapy comprising assessing the tumor histologic subtype (THS) of the tumor.
  • the method further comprises administering an anti-cancer therapy (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors) to the human subject.
  • an anti-cancer therapy e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors
  • the present disclosure also provides a method of treating a human subject afflicted with a tumor identified as having a certain THS, comprising administering an anti-cancer therapy (e.g., i) immunotherapy for a solid THS, or ii) chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar THS) in the human subject.
  • an anti-cancer therapy e.g., i) immunotherapy for a solid THS, or ii) chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar THS
  • the methods of the disclosure comprise (a) identifying a human subject afflicted with a tumor of a cancer, (b) obtaining a tumor sample from the human subject, (c) assessing the tumor histologic subtype (THS) of the tumor, and (d) administering an anti-cancer therapy (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors) to the human subject.
  • an anti-cancer therapy e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors
  • an anti-cancer therapy e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors
  • the methods of the disclosure comprise (a) identifying a population of human subjects afflicted with a tumor of a cancer, (b) obtaining a tumor sample from each human subject, (c) assessing the tumor histologic subtype (THS) of the tumor from each human subject, and (d) administering an anti-cancer therapy (e.g., immunotherapy (e.g., an immune checkpoint inhibitor, e.g., a PD-1 antagonist, a CTLA-4 antagonist, or a PD-L1 antagonist) for a solid tumor, or chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar tumor) to each human subject.
  • an anti-cancer therapy e.g., immunotherapy (e.g., an immune checkpoint inhibitor, e.g., a PD-1 antagonist, a CTLA-4 antagonist, or a PD-L1 antagonist) for a solid tumor, or chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar
  • the immunotherapy for a solid tumor can be an immunotherapy that acts as an immune check point inhibitor (e.g., a PD-1 antagonist, a CTLA-4 antagonist, or a PD-L1 antagonist).
  • an immune check point inhibitor e.g., a PD-1 antagonist, a CTLA-4 antagonist, or a PD-L1 antagonist.
  • the chemotherapy or an agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar tumor is not an immune checkpoint inhibitor (e.g., a PD-1 antagonist, a CTLA-4 antagonist, or a PD-L1 antagonist).
  • the methods of the disclosure comprise (a) treating a human subj ect afflicted with a tumor of a cancer by administering an anti-cancer therapy (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors) to the subject, (b) obtaining a tumor sample from the human subject, (c) assessing the tumor histologic subtype (THS) of the tumor, and (d) administering the same and/or a different anti-cancer therapy (e.g., immunotherapy (e.g., an immune checkpoint inhibitor, e.g., a PD-1 antagonist, a CTLA-4 antagonist, or a PD-L1 antagonist) for a solid tumor, or chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar tumor) to the human subject.
  • an anti-cancer therapy e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumor
  • the methods of the disclosure comprise (a) identifying a subject afflicted with a tumor of a cancer who develop resistance to an anti-cancer therapy (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors), (b) obtaining a tumor sample from the subject, (c) assessing the tumor histologic subtype (THS) of the tumor, (d) administering the same and/or a different anti-cancer therapy (e.g., immunotherapy (e.g., an immune checkpoint inhibitor, e.g., a PD-1 antagonist, a CTLA-4 antagonist, or a PD-L1 antagonist) for a solid tumor, or chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar tumor) to the subject.
  • an anti-cancer therapy e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar tumor
  • the methods of the disclosure comprise (a) identifying a population of human subjects afflicted with a tumor of a cancer who develop resistance to an anti-cancer therapy (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors), (b) obtaining a tumor sample from each human subject, (c) assessing the tumor histologic subtype (THS) of the tumor from each human subject, (d) administering the same and/or a different anti-cancer therapy (e.g., i) immunotherapy for a solid tumor, or ii) chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors for an ascinar tumor) to each human subject.
  • an anti-cancer therapy e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar tumors
  • TLS tumor histologic subtype
  • the human subject is afflicted with a nonsquamous non small cell lung cancer (NSCLC).
  • NSCLC nonsquamous non small cell lung cancer
  • the human subject is afflicted with a tumor from a cancer.
  • the tumor is a primary tumor, a secondary tumor, a methastatic tumor, or any combination thereof.
  • the tumor is resectable or unresectable.
  • the human subject has been diagnosed with a tumor of a nonsquamous NSCLC. In some aspects, the human subject is being treated for a nonsquamous NSCLC. In some aspects, the human subject has been previously treated for a tumor of a nonsquamous NSCLC.
  • the human subject is being treated with surgery, radiation, or any combination thereof. In some aspects, the human subject is being treated with an immunotherapy. In some aspects, the human subject is being treated with an immunotherapy and with surgery, radiation, chemotherapy or any combination thereof. In some aspects, the human subject is being treated with a chemotherapy.
  • the human subject is responsive to surgery, radiation, chemotherapy, immunotherapy, or any combination thereof. In some aspects, the human subject is not responsive to surgery, radiation, chemotherapy, immunotherapy, or any combination thereof. In some aspects, the human subject initially benefitted from surgery, radiation, chemotherapy, immunotherapy, or any combination thereof and subsequently developed resistance.
  • the human subject is responsive to an anti-cancer therapy (e.g., immunotherapy or chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors).
  • an anti-cancer therapy e.g., immunotherapy or chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors.
  • the human subject is not responsive to an anti-cancer therapy (e.g., immunotherapy or chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors).
  • the human subject initially benefitted from an anti-cancer therapy (e.g., immunotherapy or chemotherapy or agent that acts to inhibit a pathway that is upregulated in ascinar tumors) and subsequently developed resistance.
  • the tumor sample derives from a biopsy, or from a tumor resection. In some aspects, the tumor sample is a tumor sample from the lung.
  • the tumor sample is fixed in formaldehyde, formalin, glutaraldehyde, ethanol, methanol, acetone, acetic acid, acetic anhydride, osmium tetroxide, potassium di chromate, chromic acid, potassium permanganate, picrates (e.g., Bouin’s Fixative), Hepes-glutamic acid buffer and the like.
  • the tumor sample is deep-freezed, freeze- dried, or cryopreserved.
  • the tumor sample is embedded in paraffin, gelatin, agarose, or any resin which may be suitable for sectioning, including commercially available embedding media.
  • the tumor sample is stored at any point during its processing.
  • a fixed sample can be stored before embedding
  • an embedded sample can be stored before sectioning
  • a sectioned sample can be stored before staining.
  • Sample storage conditions and sample storage media are well known to those skilled in the art.
  • the tumor sample is processed by sectioning.
  • the tumor sample may be processed by sectioning by any of the means well known to those of skill in the art (e.g., microtome, vibratome, cryostat or the like).
  • the tumor sample comprises one or more tumor sections derived from a tumor tissue biopsy or from a tumor tissue resection.
  • the one or more tumor sections comprise a formalin-fixed, paraffin-embedded tumor tissue or a fresh- or fixed-frozen tumor tissue.
  • the one or more tumor sections comprise serially sectioned tumor sections.
  • the one or more tumor sections are stained by any of the means well known to those of skill in the art, for example Hematoxylin and Eosin (H&E), or immunohistochemistry (IHC).
  • H&E Hematoxylin and Eosin
  • IHC immunohistochemistry
  • the one or more tumor sections comprise one tumor section, two tumor sections, three tumor sections, four tumor sections, five tumor sections, six tumor sections, seven tumor sections, eight tumor sections, nine tumor sections, ten tumor sections, 11 tumor sections, 12 tumor sections, 13 tumor sections, 14 tumor sections, 15 tumor sections, 16 tumor sections, 17 tumor sections, 18 tumor sections, 19 tumor sections, 20 tumor sections, 21 tumor sections, 22 tumor sections, 23 tumor sections, 24 tumor sections, 25 tumor sections, 26 tumor sections, 27 tumor sections, 28 tumor sections, 29 tumor sections, or 30 tumor sections.
  • the one or more tumor sections comprise three tumor sections.
  • the one or more tumor sections comprise 15 tumor sections.
  • the one or more tumor sections comprise 18 tumor sections.
  • the one or more tumor sections comprise 20 tumor sections.
  • the one or more tumor sections comprise 21 tumor sections.
  • TLS Tumor Histologic Subtype
  • the methods as disclosed herein comprise assessing a THS.
  • the THS is assessed in a tumor sample (e.g., a lung tumor sample).
  • the THS is assessed in a tumor sample obtained from the subject (e.g., a tumor sample taken from the lung of the subject).
  • the tumor sample is (a) obtained from the patient, (b) fixed in a selected fixative, (c) embedded in a selected embedding medium, (d) sectioned by a selected mean, (e) optionally stained, and (f) analyzed (e.g., by microscopy).
  • the tumor sample is stained before sectioning. In some aspects, the tumor sample is stained after sectioning.
  • the tumor sample can be stained by any mean well known to those of skill in the art.
  • the tumor sample is stained by Hematoxylin and eosin (H&E), Chrome alum/hematoxylin, Isamin blue/eosin, Van Gieson, Toluidine blue, Alcian blue, Giemsa, Reticulin, Nissl, Orcein, Sudan black B, Sudan Black and osmium, Masson’s tri chrome, Mallory’s tri chrome, Azan trichrome, Cason’s trichrome, PAS (Periodic acid Schiff), Weigert’s resorcin fuchsin (Weigert’s elastic), Wright and Wright Giemsa stain, Aldehyde fuchsin, Silver and gold, immunohistochemistry, immunofluorescence, and the like. Immunohisto
  • the tumor sample is mounted in the appropriate mounting medium after staining.
  • the tumor sample is analyzed by microscopy after staining.
  • the tumor sample can be analyzed by any microscopy technique well known to those of skill in the art, such as Stereo Microscopes, Compound Microscopes, Inverted Microscopes, Metallurgical Microscopes, Polarizing Microscopes, Digital Microscopes, Electron Microscopes, Scanning Probe Microscopes, Confocal Microscope, Multiphoton Microscope and the like.
  • the tumor sample is analyzed by Inverted Microscopes.
  • the grading of cancer is a histological method intended to help predict prognosis based on specific morphological features.
  • tumor histologic subtype “tumor histological subtype,” or “THS,” generally refer to descriptions of a tumor based on the type and/or morphology of the neoplasm cells. Grading systems and THS are different for each type of cancer.
  • cribriform defined as nests of neoplastic cells with sieve-like perforations
  • fused gland defined as poorly formed fused glands without intervening stroma or in a ribbon-like formation with irregular borders and single cells infiltrating desmoplastic stroma
  • Pulmonary adenocarcinomas are histologically heterogeneous and present with multiple combinations of patterns and proportions. When classified by the predominant pattern only, the acinar subtype is the most prevalent (estimated at 40%-50% of patients) and carries the widest spectrum of prognoses (Yoshizawa A. Motoi N. Riely G.J. et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol. 2011; 24: 653- 664; Yoshizawa A. Sumiyoshi S. Sonobe M. et al.
  • NSCLC THS can be briefly described as follows:
  • Lepidic type II pneumocytes and club cells proliferate to line alveolar walls; lacks architectural complexity; no lymphovascular or perineural invasion (J Thorac Dis 2017;9:2142, J Thorac Oncol 2011;6:244).
  • Acinar gland forming; round / oval glands invading the stroma (usually fibrous) (J Thorac Oncol 2020;15: 1599, J Thorac Oncol 2011;6:244).
  • Papillary malignant cuboidal / columnar cells replace alveolar lining; contains fibrovascular cores (J Thorac Oncol 2011;6:244).
  • Micropapillary ill defined projection / tufting that lacks fibrovascular cores (J Thorac Oncol 2011;6:244).
  • the tumor samples are assessed or analyzed by a pathologist, a physician, or other qualified person such as a researcher, a laboratory technician, or a healthcare provider.
  • an automated method is used to analyze (or assist in analysis of) the tumor samples.
  • the tumor samples are further analyzed using any suitable algorithm, for example, a machine-learning algorithm.
  • assessing a THS status of a tumor can be achieved without obtaining a tumor sample.
  • a THS status is measured or assessed by, for example, reviewing a report of test results from a laboratory.
  • the methods up to, and including, measuring a THS status provides an intermediate or definitive result that may be provided to a physician or other healthcare provider for use in identifying a human subject suitable anti-cancer therapy or anti-cancer therapies (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar or solid tumors) for treating cancer.
  • the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other aspects, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician.
  • the methods as disclosed herein further comprise assessing a tumor in a certain stage, or assessing a stage of the tumor.
  • the stage of the tumor is assessed in a tumor sample (e.g., a lung tumor sample).
  • the stage of the tumor is assessed in a tumor sample obtained from the subject (e.g., a tumor sample taken from the lung of the subject).
  • the tumor sample is (a) obtained from the patient, (b) fixed in a selected fixative, (c) embedded in a selected embedding medium, (d) sectioned by a selected mean, (e) optionally stained, and (f) analyzed (e.g., by microscopy).
  • the tumor sample is stained before sectioning. In some aspects, the tumor sample is stained after sectioning.
  • the tumor sample can be stained by any mean well known to those of skill in the art.
  • the tumor sample is stained by Hematoxylin and eosin (H&E), Chrome alum/hematoxylin, Isamin blue/eosin, Van Gieson, Toluidine blue, Alcian blue, Giemsa, Reticulin, Nissl, Orcein, Sudan black B, Sudan Black and osmium, Masson’s tri chrome, Mallory’s tri chrome, Azan trichrome, Cason’s trichrome, PAS (Periodic acid Schiff), Weigert’s resorcin fuchsin (Weigert’s elastic), Wright and Wright Giemsa stain, Aldehyde fuchsin, Silver and gold, immunohistochemistry, immunofluorescence, and the like. Immunohisto
  • the tumor sample is mounted in the appropriate mounting medium after staining.
  • the tumor sample is analyzed by microscopy after staining.
  • the tumor sample can be analyzed by any microscopy technique well known to those of skill in the art, such as Stereo Microscopes, Compound Microscopes, Inverted Microscopes, Metallurgical Microscopes, Polarizing Microscopes, Digital Microscopes, Electron Microscopes, Scanning Probe Microscopes, Confocal Microscope, Multiphoton Microscope and the like.
  • the tumor sample is analyzed by Inverted Microscopes.
  • Tumor staging is a method intended to help predict prognosis based on specific cancer features.
  • the tumor features include anatomic and/or nonanatomic features.
  • General tumor staging rules are known to those skilled in the art (see, e.g., Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized” approach to cancer staging. CA Cancer J Clin. 2017 Mar; 67(2): 93 -99.) and can be applied across all disease sites and along the tumor staging continuum; including clinical, pathological, posttherapy/postneoadjuvant therapy, recurrence/retreatment, and autopsy classifications.
  • stage of a tumor describes how much and where the tumor is in the body.
  • stage 0 also called carcinoma in situ, or CIS.
  • Other stages range from I (1) through IV (4).
  • the lower the number the less the tumor has spread.
  • a higher number, such as stage IV means tumor has spread more; and within a stage, an earlier letter (or number) means a lower stage.
  • the cancer staging is performed in accordance to a TNM cancer staging system.
  • the TNM cancer staging system is known to those skilled in the art (see, e.g., Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized” approach to cancer staging. CA Cancer J Clin. 2017 Mar;67(2):93-99; and Lababede O, Meziane MA. The Eighth Edition of TNM Staging of Lung Cancer: Reference Chart and Diagrams. Oncologist. 2018 Jul;23(7):844-848; for TNM staging of lung cancer).
  • the TNM cancer staging system has three components: the features/extent of the primary tumor (T), regional lymph node(s) involvement (N), and distant metastases (M).
  • TNM cancer staging can be as follows:
  • Tx Tumor that is proven histopathologically (malignant cells in bronchopulmonary secretions/washings) but cannot be assessed or is not demonstrable radiologically or bronchoscopically.
  • Local invasion direct invasion of chest wall (including superior sulcus tumors), parietal pleura (PL3), phrenic nerve, or parietal pericardium. Separate tumor nodule(s) in the same lobe of the primary tumor.
  • T4 Any of the following characteristics: Size>7 cm. Airway location: invasion of the carina or trachea. Local invasion: diaphragm, mediastinum, heart, great vessels, recurrent laryngeal nerve, esophagus or vertebral body. Separate tumor nodule(s) in an ipsilateral different lobe of the primary tumor.
  • Nx Regional lymph nodes cannot be evaluated.
  • Nl Involvement of ipsilateral peribronchial and/or ipsilateral hilar lymph nodes (includes direct extension to intrapulmonary nodes).
  • N2 Involvement of the ipsilateral mediastinal and/or subcarinal lymph nodes.
  • N3 Involvement of any of the following lymph node groups: contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular nodes.
  • Ml Presence of distant metastasis. Subdivisions: Mia (separate tumor nodule(s) in a contralateral lobe to that of the primary tumor or tumors with pleural or pericardial nodules or malignant effusion); Mlb (single extrathoracic metastasis); Mlc (multiple extrathoracic metastases to one or more organs).
  • the stage of a cancer is determined as follows:
  • IA1 Tlmi - NO - MO or IA1 : Tla - NO - MO
  • IA2 Tib - NO - MO
  • IA3 Tic - NO - MO
  • IIB Tla/Tlb/Tlc - Nl - MO or IIB: T2a/T2b - Nl - MO or IIB: T3 - NO - MO
  • IIIA Tla/Tlb/Tlc - N2 - MO or IIIA: T2a/T2b - N2 - MO or IIIA: T3 - Nl - MO or IIIA: T4 - NO or Nl - MO
  • IIIB Tla/Tlb/Tlc - N3 - MO or IIIB: T2a/T2b - N3 - MO or IIIB: T3 - N2 - MO or IIIB: T4 - N2 -
  • IIIC T3 - N3 - MO or IIIC: T4 - N3 - MO
  • IVA Any T - Any N - Mia or IVA: Any T - Any N - Mlb
  • a cancer that has not spread from the primary site (place where it started) to other places in the body is called nonmetastatic cancer.
  • a cancer that spreads from where it started to a distant part of the body is called metastatic cancer.
  • metastatic cancer corresponds to a stage IV cancer.
  • the NSCLC is an Occult (hidden) NSCLC, a stage 0 NSCLC, a stage IA1 NSCLC, a stage IA2 NSCLC, a stage IA3 NSCLC, a stage IB NSCLC, a stage IIA NSCLC, a stage IIB NSCLC, a stage IIIA NSCLC, a stage IIIB NSCLC, a stage IIIC NSCLC, a stage IVA NSCLC, or a stage IVB NSCLC.
  • the NSCLC is a nonmetastatic NSCLC.
  • the NSCLC is a metastatic NSCLC.
  • the tumor samples are assessed or analyzed by a pathologist, a physician, or other qualified person such as a researcher, a laboratory technician, or a healthcare provider.
  • an automated method is used to analyze (or assist in analysis of) the tumor samples.
  • the tumor samples are further analyzed using any suitable algorithm, for example, a machine-learning algorithm.
  • assessing a stage of the cancer can be achieved without obtaining a tumor sample.
  • a stage of the cancer is measured or assessed by, for example, reviewing a report of test results from a laboratory.
  • the methods up to, and including, measuring a stage of the cancer status provides an intermediate or definitive result that may be provided to a physician or other healthcare provider for use in identifying a human subject suitable anti-cancer therapy or anti-cancer theraies (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar or solid tumors) for treating cancer.
  • the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other aspects, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician.
  • the methods as disclosed herein further comprise measuring an Inflammation Gene Expression Signature. In some aspects, the methods as disclosed herein comprise measuring an Inflammation Gene Expression Signature in a tumor sample. In some aspects, the methods as disclosed herein comprise measuring an Inflammation Gene Expression Signature in a tumor sample obtained from the subject.
  • Inflammation Gene Expression Signature is an analysis of expression in the tumor microenvironment of gene transcripts associated with the presence of an immune response (e.g., genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance). Gene expression in the tumor microenvironment maybe assessed by various technology platforms, and different, but highly correlated, gene transcripts.
  • an immune response e.g., genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance.
  • Inflammation Gene Expression Signature is a transcriptomic analysis of a tumor’s transcriptome and, thus, can be measured by applying transcriptomic methods well known to those of skill in the art. Any method known in the art for measuring the expression of a particular gene or a panel of genes can be used in the methods of the present disclosure. In some aspects, the expression of one or more of the genes in the panel of genes is determined by detecting the presence of mRNA transcribed from the gene, the presence of a protein encoded by the gene, or both.
  • Inflammation Gene Expression Signature can be measured by Northern blotting, Wester blotting, polymerase chain reaction (e.g., Reverse-Transcriptase (RT- PCR), Real-time PCR, quantitative qPCR), DNA microarray, and RNA-Seq, RNA in situ hybridization, immunohistochemistry, and the like. In some aspects the measuring is conducted in vitro.
  • the expression of one or more of the genes is determined by measuring the level of gene mRNA in a sample obtained from the subject. Any method known in the art can be used to measure the level of the gene mRNA. In some aspects, the gene mRNA is measured using reverse transcriptase PCR. In some aspects, the gene mRNA is measured using RNA in situ hybridization.
  • the expression of one or more of the genes is determined by measuring the level of protein expressed from the gene in a sample obtained from the subject. Any method known in the art can be used to measure the level of the protein.
  • the protein is measured using an immunohistochemistry (IHC) assay.
  • IHC immunohistochemistry
  • the IHC is an automated IHC.
  • the expression of one or more of the genes of the inflammatory gene panel is normalized relative to the expression of one or more housekeeping genes.
  • the one or more housekeeping genes comprises any housekeeping gene disclosed herein or any combination thereof.
  • raw gene expression values are normalized following standard gene expression profiling (GEP) protocols.
  • GEP gene expression profiling
  • gene expression signature scores can be calculated as the median or average of the log2 -transformed normalized and scaled expression values across all of the target genes in the signature, and presented on a linear scale.
  • scores have positive or negative values, depending on whether gene expression is up- or down-regulated under a particular condition.
  • a low signature score is characterized by a signature score that is lower than a reference signature score.
  • the reference inflammatory signature score is an average signature score.
  • the average signature score is determined by measuring the expression of the genes present in the panel of genes in tumor samples obtained from a population of subjects, and calculating the average for the population of subjects.
  • each member of the population of subj ects is afflicted with a tumor. In some aspects, each member of the population of subjects is not afflicted with a tumor. In some aspects, some member of the population of subjects are afflicted with a tumor. In some aspects, not all of the members of the population of subjects are afflicted with a tumor.
  • each member of the population of subjects is afflicted with a same tumor. In some aspects, each member of the population of subjects is not afflicted with a same tumor. In some aspects, some member of the population of subjects are afflicted with a same tumor. In some aspects, not all of the members of the population of subjects are afflicted with a same tumor.
  • each member of the population of subjects is afflicted with the same tumor as the subject of the methods disclosed herein. In some aspects, each member of the population of subjects is not afflicted with the same tumor as the subject of the methods disclosed herein. In some aspects, some member of the population of subjects are afflicted with the same tumor as the subject of the methods disclosed herein. In some aspects, not all of the members of the population of subjects are afflicted with the same tumor as the subject of the methods disclosed herein.
  • each member of the population of subjects is afflicted with a tumor of a non-small cell lung cancer. In some aspects, each member of the population of subjects is not afflicted with a tumor of a non-small cell lung cancer. In some aspects, some member of the population of subjects are afflicted with tumor of a non-small cell lung cancer. In some aspects, not all of the members of the population of subjects are afflicted with tumor of a non-small cell lung cancer.
  • a low signature score is characterized by a signature score that is at less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% that of the average signature score.
  • a low signature score is characterized by a signature score that is at less than about 95% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 90% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 85% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 80% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 75% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 70% that of the average signature score.
  • a low signature score is characterized by a signature score that is at less than about 65% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 60% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 55% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 50% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 45% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 40% that of the average signature score.
  • a low signature score is characterized by a signature score that is at less than about 35% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 30% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 25% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 20% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 15% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 10% that of the average signature score.
  • a low signature score is characterized by a signature score that is at less than about 9% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 8% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 7% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 6% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 5% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 4% that of the average signature score.
  • a low signature score is characterized by a signature score that is at less than about 3% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 2% that of the average signature score. In some aspects, a low signature score is characterized by a signature score that is at less than about 1% that of the average signature score.
  • measuring Inflammation Gene Expression Signature can comprise measuring expression of one or more of a panel of genes comprising, but not limited to, CCL2, CCL3, CCL4, CCL5, CCR2, CCR5, CD27, CD274, CD276, CD28, CD 3, CD73, CD80, CD86, CD8A, CMKLR1, CSF1R, CTLA-4, CXCL10, CXCL11, CXCL9, CXCRI, CXCR2, CXCR6, EP4, Galectin-9, GITR, GITRL, GZMA, GZMK, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA- DQA1, HLA-DRA, HLA-DRB1, HLA-E, ICOS, ICOS-L, IDO1, IFNG, IL8, IRF1, KIR-Liri, LAG3, Nectin-2, NKG2D, NKG7, 0X40, OX40L, Pan-
  • the gene panel comprises at least 1, at least 2, at least 3, at leaset 4, or at least 5 genes selected from the group consisting of CCL2, CCL3, CCL4, CCL5, CCR2, CCR5, CD27, CD274, CD276, CD28, CD 3, CD73, CD80, CD86, CD8A, CMKLR1, CSF1R, CTLA-4, CXCL10, CXCL11, CXCL9, CXCR1, CXCR2, CXCR6, EP4, Galectin-9, GITR, GITRL, GZMA, GZMK, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DQA1, HLA-DRA, HLA- DRB1, HLA-E, ICOS, ICOS-L, IDO1, IFNG, IL8, IRF1, KIR-Liri, LAG3, Nectin-2, NKG2D, NKG7, 0X40, OX40L, Pan-
  • the panel of genes comprises at least 5 genes, wherein the at least 5 genes comprise: (i) at least one gene selected from the group consisting of TDO2, PD1, CTLA- 4, Pan-KIR-L, Pan-KIR-S, ICOS-L, CCR2, CD73, CSF1R, GITR, GITRL, IL8, CXCR1, CD80, CD86, Galectin -9, 0X40, OX40L, STING, TIMS, NKG2D, PVR, EP4, CXCR2, Nectin-2, and KIR- Lirr, and (ii) 2 additional genes, 3 additional genes, 4 additional genes, 5 additional genes, 6 additional genes, 7 additional genes, 8 additional genes, 9 additional genes, 10 additional genes, 11 additional genes, 12 additional genes, 13 additional genes, 14 additional genes, 15 additional genes, 16 additional genes, or 17 additional genes.
  • the gene panel consists essentially of (or consists of) (i) CD274 (PD-L1) andA4G3, and (ii) 2 additional genes, 3 additional genes, 4 additional genes, 5 additional genes, 6 additional genes, 7 additional genes, 8 additional genes, 9 additional genes, 10 additional genes, 11 additional genes, 12 additional genes, 13 additional genes, 14 additional genes, 15 additional genes, 16 additional genes, 17 additional genes, 18 additional genes, 19 additional genes, 20 additional genes, 21 additional genes, 22 additional genes, 23 additional genes, 24 additional genes, 25 additional genes, 26 additional genes, 27 additional genes, 28 additional genes, 29 additional genes, 30 additional genes, 31 additional genes, 32 additional genes, 33 additional genes, 34 additional genes, 35 additional genes, 36 additional genes, 37 additional genes, 38 additional genes, 39 additional genes, 40 additional genes, 41 additional genes, 42 additional genes, 43 additional genes, 44 additional genes, 45 additional genes, 46 additional genes, 47 additional genes, 48 additional genes, 49 additional genes, 50 additional genes, 51 additional genes, 52 additional genes, 53 additional genes, 54 additional genes, 55 additional genes,
  • the panel of genes comprises at least one housekeeping gene.
  • a housekeeping gene is a gene that is expressed at a nearly constant level across various cell types. As such, the expression of a house keeping gene can be relative to the number of cells in a sample, acting as a means of normalizing the expression of other variable genes.
  • the panel of genes comprises at least 2 housekeeping genes, at least 3 housekeeping genes, at least housekeeping genes, at least 4 housekeeping genes, at least 5 housekeeping genes, at least 6 housekeeping genes, at least 7 housekeeping genes, at least 8 housekeeping genes, at least 9 housekeeping genes, at least 10 housekeeping genes, at least 11 housekeeping genes, at least 12 housekeeping genes, at least 13 housekeeping genes, at least 14 housekeeping genes, at least 15 housekeeping genes, at least 16 housekeeping genes, at least 17 housekeeping genes, at least 18 housekeeping genes, at least 19 housekeeping genes, at least 20 housekeeping genes, at least 21 housekeeping genes, at least 22 housekeeping genes, at least 23 housekeeping genes, at least 24 housekeeping genes, at least 25 housekeeping genes, at least 26 housekeeping genes, at least housekeeping genes, at least 27 housekeeping genes, at least 28 housekeeping genes, at least 29 housekeeping genes, at least 30 housekeeping genes, at least 35 housekeeping genes, at least 40 housekeeping genes, at least 45 housekeeping genes, at least 50 housekeeping genes, at least 55, at least
  • the panel of genes comprises at least 2 housekeeping genes. In some aspects, the panel of genes comprises at least 3 housekeeping genes. In some aspects, the panel of genes comprises at least 4 housekeeping genes. In some aspects, the panel of genes comprises at least 5 housekeeping genes. In some aspects, the panel of genes comprises at least 6 housekeeping genes. In some aspects, the panel of genes comprises at least 7 housekeeping genes. In some aspects, the panel of genes comprises at least 8 housekeeping genes. In some aspects, the panel of genes comprises at least 9 housekeeping genes. In some aspects, the panel of genes comprises at least 10 housekeeping genes. In some aspects, the panel of genes comprises at least 11 housekeeping genes. In some aspects, the panel of genes comprises at least 12 housekeeping genes. In some aspects, the panel of genes comprises at least 13 housekeeping genes. In some aspects, the panel of genes comprises at least 14 housekeeping genes. In some aspects, the panel of genes comprises at least 15 housekeeping genes.
  • any housekeeping genes known in the art can be used in the panel of genes disclosed herein.
  • the housekeeping genes are selected from the group consisting of ACTB, ATP5F1, DDX5, EEF1G, GAPDH, NCL, OAZ1, PPIA, RPL38, RPL6, RPS7, SLC25A3, 801)1, YWHAZ. and any combination thereof.
  • the panel of genes comprises at least one control gene.
  • the panel of genes comprises at least 2 control genes, at least 3 control genes, at least control genes, at least 4 control genes, at least 5 control genes, at least 6 control genes, at least 7 control genes, at least 8 control genes, at least 9 control genes, at least 10 control genes, at least 11 control genes, at least 12 control genes, at least 13 control genes, at least 14 control genes, at least
  • control genes 15 control genes, at least 16 control genes, at least 17 control genes, at least 18 control genes, at least 19 control genes, at least 20 control genes, at least 21 control genes, at least 22 control genes, at least 23 control genes, at least 24 control genes, at least 25 control genes, at least 26 control genes, at least control genes, at least 27 control genes, at least 28 control genes, at least 29 control genes, at least 30 control genes, at least 35 control genes, at least 40 control genes, at least 45 control genes, at least 50 control genes, at least 55 control genes, at least 60 control genes, at least 65 control genes, at least 70 control genes, at least 75 control genes, at least 80 control genes, at least 85 control genes, at least 85 control genes, at least 90 control genes, at least 95 control genes, or at least 100 control genes.
  • the panel of genes comprises at least 2 control genes. In some aspects, the panel of genes comprises at least 3 control genes. In some aspects, the panel of genes comprises at least 4 control genes. In some aspects, the panel of genes comprises at least 5 control genes. In some aspects, the panel of genes comprises at least 6 control genes. In some aspects, the panel of genes comprises at least 7 control genes. In some aspects, the panel of genes comprises at least 8 control genes. In some aspects, the panel of genes comprises at least 9 control genes. In some aspects, the panel of genes comprises at least 10 control genes. In some aspects, the panel of genes comprises at least 11 control genes. In some aspects, the panel of genes comprises at least 12 control genes. In some aspects, the panel of genes comprises at least 13 control genes. In some aspects, the panel of genes comprises at least 14 control genes. In some aspects, the panel of genes comprises at least 15 control genes. In some aspects, the panel of genes comprises at least
  • the panel of genes comprises at least 17 control genes. In some aspects, the panel of genes comprises at least 18 control genes. In some aspects, the panel of genes comprises at least 19 control genes. In some aspects, the panel of genes comprises at least 20 control genes. In some aspects, the control genes are selected from the group consisting of ANTI, ANT2, ANT3, ANT4, PCL-1, PCL-10, PCL-2, PCL-3, PCL-4, PCL-5, PCL-6, PCL-7, PCL-8, PCL- 9, POS1, POS2, POS3, POS4, and any combination thereof.
  • the panel of genes comprises CCL2, CCL3, CCL4, CCL5, CCR2, CCR5, CD27, CD274, CD276, CD28, CD3, CD73, CD80, CD86, CD8A, CMKLR1, CSF1R, CTI.A-4, CXCL10, CXCLU, CXCL9, CXCR1, CXCR2, CXCR6, EP4, Galectin -9, GITR, GITRI., GZMA, GZMK, HIA-DMA, HLA-DMB, HIA-DOA, HLA-DOB, HLA-DQA1, HIA-DRA, HLA- DRB1, HIA-E, ICOS, ICOS-L, IDO1, IFNG, IL8, IRF1, KIR-Liri, LAGS, Nectin-2, NKG2D, NKG7, 0X40, OX40L, Pan-KIR-L, Pan-KIR-S, PD1,
  • the panel of genes comprises CCL2, CCL3, CCL4, CCL5, CCR2, CCR5, CD27, CD274, CD276, CD28, CDS, CD73, CD80, CD86, CD8A, CMKLR1, CSF1R, CTLA-4, CXCL10, CXCLU, CXCL9, CXCR1, CXCR2, CXCR6, EP4, Galectin -9, GITR, GITRL, GZMA, GZMK, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DQA1, HLA-DRA, HLA- DRB1, HLA-E, ICOS, ICOS-L, IDO1, IFNG, IL8, IRF1, KIR-Liri, LAGS, Nectin-2, NKG2D, NKG7, 0X40, OX40L, Pan-KIR-L, Pan-KIR-S, PD1, PDCD1LG2, PR
  • the panel of genes consists essentially of CCL2, CCL3, CCL4, CCL5, CCR2, CCR5, CD27, CD274, CD276, CD28, CDS, CD73, CD80, CD86, CD8A, CMKLR1, CSF1R, CTLA-4, CXCL10, CXCLU, CXCL9, CXCR1, CXCR2, CXCR6, EP4, Galectin -9, GITR, GITRL, GZMA, GZMK, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-E, ICOS, ICOS-L, IDO1, IFNG, IL8, IRF1, KIR-Liri, LAGS, Nectin-2, NKG2D, NKG7, 0X40, OX40L, Pan-KIR-L, Pan-KIR-S, PD1, PDCD
  • the panel of genes consists of CCL2, CCL3, CCL4, CCL5, CCR2, CCR5, CD27, CD274, CD276, CD28, CDS, CD73, CD80, CD86, CD8A, CMKLR1, CSF1R, CTLA-4, CXCL10, CXCLU, CXCL9, CXCR1, CXCR2, CXCR6, EP4, Galectin -9, GITR, GITRL, GZMA, GZMK, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DQA1, HLA-DRA, HLA- DRB1, HLA-E, ICOS, ICOS-L, IDO1, IFNG, IL8, IRF1, KIR-Liri, LAGS, Nectin-2, NKG2D, NKG7, 0X40, OX40L, Pan-KIR-L, Pan-KIR-S, PD1, PDCD1LG
  • Inflammation Gene Expression Signature can be measured in any tumor sample as described herein.
  • Inflammation Gene Expression Signature can be measured by RNA- Seq of a tumor sample, such as a formalin-fixed paraffin-embedded tumor sample.
  • the tumor samples are analyzed by a pathologist, a physician, or other qualified person such as a researcher, a laboratory technician, or a healthcare provider.
  • an automated method is used to analyze the tumor samples.
  • the tumor samples are further analyzed using any suitable algorithm, for example, a machine-learning algorithm.
  • the measuring an Inflammation Gene Expression Signature can be achieved without obtaining a tumor sample.
  • an Inflammation Gene Expression Signature is measured by, for example, reviewing a report of test results from a laboratory.
  • the steps of the methods up to, and including, measuring an Inflammation Gene Expression Signature provides an intermediate or definitive result that may be provided to a physician or other healthcare provider for use in identifying a human subject suitable anti-cancer therapy or anti-cancer therapies (e.g., immunotherapy, chemotherapy, or agent that acts to inhibit a pathway that is upregulated in ascinar or solid tumors) for treating cancer.
  • the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other aspects, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician.
  • TMB Tumor mutational burden
  • the methods as disclosed herein further comprise measuring a tumor mutational burden (TMB) status.
  • the methods as disclosed herein comprise measuring a tumor mutational burden (TMB) status in a tumor sample.
  • the methods as disclosed herein comprise measuring a tumor mutational burden (TMB) status in a tumor sample obtained from the subject.
  • TMB is a genetic analysis of a tumor’s genome and, thus, can be measured by applying sequencing methods well known to those of skill in the art. The tumor DNA can be compared with DNA from patient-matched normal tissue to eliminate germline mutations or polymorphisms.
  • TMB is determined by sequencing tumor DNA using a high- throughput sequence technique, e.g., next-generation sequencing (NGS) or an NGS-based method.
  • NGS-based method is selected from whole genome sequencing (WGS), whole exome sequencing (WES), or comprehensive genomic profiling (CGP) of cancer gene panels such as FOUND ATIONONE® CDXTM and MSK-IMPACT clinical tests.
  • TMB refers to the number of somatic mutations per megabase (Mb) of DNA sequenced.
  • TMB is measured using the total number of nonsynonymous mutations, e.g., missense mutation (z.e., changing a particular amino acid in the protein) and/or nonsense (causing premature termination and thus truncation of the protein sequence), identified by normalizing matched tumor with germline samples to exclude any inherited germline genetic alterations.
  • TMB is measured using the total number of missense mutations in a tumor.
  • tissue sample for example, a minimum of 10 slides
  • TMB is expressed as NsMs per megabase (NsM/Mb). 1 megabase represents 1 million bases.
  • the TMB status can be a numerical value or a relative value, e.g. , high, medium, or low; within the highest fractile, or within the top tertile, of a reference set.
  • the TMB status is a high TMB.
  • a “high TMB” refers to a number of somatic mutations in a tumor’ s genome that is above a number of somatic mutations that is normal or average.
  • a high TMB has a score of at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, at least 245, at least 250, at least 255, at least 260, at least 265, at least 270, at least 275, at least 280, at least 285, at least 290, at least 295, at least 300, at least 305, at least 310, at least 315, at least 320, at least 325, at least 330, at least 335, at least 340, at least 345, at least 350, at least 355, at least 360, at least 365, at least 370, at least 375, at least 380, at least 385, at least 390, at least 395, at least 400, at least 405, at
  • a high TMB status has a score of at least at least 221, at least 222, at least 223, at least 224, at least 225, at least 226, at least 227, at least 228, at least 229, at least 230, at least 231, at least 232, at least 233, at least 234, at least 235, at least 236, at least 237, at least 238, at least 239, at least 240, at least 241, at least 242, at least 243, at least 244, at least 245, at least 246, at least 247, at least 248, at least 249, or at least 250.
  • a high TMB status has a score of at least 243.
  • a “high TMB” refers to a TMB within the highest fractile of the reference TMB value.
  • all subjects with evaluable TMB data are grouped according to fractile distribution of TMB, z.e., subjects are rank ordered from highest to lowest number of genetic alterations and divided into a defined number of groups.
  • all subjects with evaluable TMB data are rank ordered and divided into thirds and a “high TMB” is within the top tertile of the reference TMB value.
  • the tertile boundaries are 0 ⁇ 100 genetic alterations; 100 to 243 genetic alterations; and > 243 genetic alterations. It should be understood that, once rank ordered, subjects with evaluable TMB data can be divided into any number of groups, e.g., quartiles, quintiles, etc.
  • a “high TMB” refers to a TMB of at least about 20 mutations/tumor, at least about 25 mutations/tumor, at least about 30 mutations/tumor, at least about 35 mutations/tumor, at least about 40 mutations/tumor, at least about 45 mutations/tumor, at least about 50 mutations/tumor, at least about 55 mutations/tumor, at least about 60 mutations/tumor, at least about 65 mutations/tumor, at least about 70 mutations/tumor, at least about 75 mutations/tumor, at least about 80 mutations/tumor, at least about 85 mutations/tumor, at least about 90 mutations/tumor, at least about 95 mutations/tumor, or at least about 100 mutations/tumor.
  • a “high TMB” refers to a TMB of at least about 105 mutations/tumor, at least about 110 mutations/tumor, at least about 115 mutations/tumor, at least about 120 mutations/tumor, at least about 125 mutations/tumor, at least about 130 mutations/tumor, at least about 135 mutations/tumor, at least about 140 mutations/tumor, at least about 145 mutations/tumor, at least about 150 mutations/tumor, at least about 175 mutations/tumor, or at least about 200 mutations/tumor.
  • a tumor having a high TMB has at least about 100 mutations/tumor.
  • “high TMB” can also be referred to as the number of mutations per megabase of genome sequenced, e.g, as measured by a mutation assay, e.g, FOUND ATIONONE® CDXTM assay or TruSight Oncology (TSO) 500 Assay.
  • the high TMB refers to at least about 9, at least about 10, at least about 11, at least 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, or at least about 20 mutations per megabase of genome as measured by a FOUND ATIONONE® CDXTM assay.
  • the “high TMB” refers to at least 10 mutations per megabase of genome sequenced by a FOUND ATIONONE® CDXTM assay or TruSight Oncology 500 Assay.
  • the term “medium TMB” refers to a number of somatic mutations in a tumor’s genome that is at or around a number of somatic mutations that is normal or average and the term “low TMB” refers to a number of somatic mutations in a tumor’s genome that is below a number of somatic mutations that is normal or average.
  • a “high TMB” has a score of at least 243
  • a “medium TMB” has a score of between 100 and 242
  • a “low TMB” has a score of less than 100 (or between 0 and 100).
  • the “medium or low TMB” refers to less than 9 mutations per megabase of genome sequenced, e.g., as measured by a FOUND ATIONONE® CDXTM assay.
  • Microsatellite instability is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR).
  • MMR DNA mismatch repair
  • the presence of MSI represents phenotypic evidence that MMR is not functioning normally.
  • the genetic basis for instability in MSI tumors is an inherited germline alteration in any one of the five human MMR genes: MSH2, MLH1, MSH6, PMS2, and PMS1.
  • the subject receiving tumor treatment has a high degree of microsatellite instability (MSI-H) and has at least one mutation in genes MSH2, MLH1, MSH6, PMS2, or PMS1.
  • subjects receiving tumor treatment within a control group have no microsatellite instability (MSS or MSI stable) and has no mutation in genes MSH2, MLH1, MSH6, PMS2, and PMS1.
  • the tumor samples are analyzed by a pathologist, a physician, or other qualified person such as a researcher, a laboratory technician, or a healthcare provider.
  • an automated method is used to analyze the tumor samples.
  • the tumor samples are further analyzed using any suitable algorithm, for example, a machine-learning algorithm.
  • the measuring a tumor mutational burden (TMB) status can be achieved without obtaining a tumor sample.
  • a tumor mutational burden (TMB) status is measured by, for example, reviewing a report of test results from a laboratory.
  • the steps of the methods up to, and including, measuring a tumor mutational burden (TMB) status provides an intermediate or definitive result that may be provided to a physician or other healthcare provider for use in identifying a human subject suitable anti-cancer therapy or anti-cancer therapies (e.g., immunotherapy or chemotherapy) for treating cancer.
  • the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other aspects, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician.
  • the methods as disclosed herein further comprise measuring PD- L1 (e.g., membranous PD-L1) expression. In some aspects, the methods as disclosed herein comprise measuring PD-L1 (e.g., membranous PD-L1) expression in a tumor sample. In some aspects, the methods as disclosed herein comprise measuring PD-L1 (e.g., membranous PD-L1) expression in a tumor sample obtained from the subject.
  • PD-L1 expression can be measured by any method well known to those of skill in the art. For example, can be measured by Northern blotting, Wester blotting, polymerase chain reaction (e.g., Reverse-Transcriptase (RT-PCR), Real-time PCR, quantitative qPCR), DNA microarray, and RNA-Seq, RNA in situ hybridization, immunohistochemistry, and the like.
  • RT-PCR Reverse-Transcriptase
  • qPCR quantitative qPCR
  • membranous PD-L1 expression in the tumor is assayed by immunohistochemistry (H4C), e.g., with the mAb 28-8.
  • H4C immunohistochemistry
  • the antibody is disclosed in Application No. 62/479,817; 62/582,146; PCT/US2018/025518 published on October 4, 2018; 16/499,540 published on April 8, 2021; 18/063,015.
  • the tumor is PD-L1 positive.
  • PD-L1 expression according to the disclosure can be determined by measuring the frequency of tumor cells expressing PD-L1 in the tumor sample (e.g., by immunohistochemistry). In some aspects, PD-L1 expression is calculated as (i) the number tumor cells expressing PD-L1 divided by (ii) the total number of cells in the tumor sample. In some aspects, PD-L1 expression is calculated as (i) the number tumor cells expressing PD-L1 divided by (ii) the tumor area (mm 2 ) of the tumor sample.
  • one tumor section of the tumor sample is stained for PD-L1.
  • the tumor section is further stained for a tumor antigen.
  • the tumor antigen is Pan cytokeratin (CK).
  • the tumor sample comprises a first tumor section stained for the PD-L1, and a second tumor section stained for a tumor antigen.
  • the first tumor section, and the second tumor section are serially sectioned from the tumor sample.
  • the tumor sample comprises a first group of tumor sections (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 tumor sections) stained for the PD-L1 and a second group of tumor sections (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 tumor sections) stained for a tumor antigen.
  • the first group and the second group of tumor sections are serially sectioned from the tumor sample.
  • PD-L1 expression is determined by quantitative spatial profiling.
  • the quantitative spatial profiling is digital spatial analysis.
  • a PD-L1 positive tumor or PD-L1 expression positive tumor means that at least about 0.001%, at least about 0.01%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 1.1%, at least about 1.2%, at least about 1.3%, at least about 1.4%, at least about 1.5%, at least about 1.6%, at least about 1.7%, at least about 1.8%, at least about 1.9%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%
  • the PD-L1 positive tumor or PD-L1 expression positive tumor can also be referred to herein as tumor expressing PD-L1.
  • the PD- L1 positive tumor or PD-L1 expression positive tumor means that at least about 0.1% to at least about 20% of the total number of cells express PD-L1.
  • the PD-L1 positive tumor or PD-L1 expression positive tumor means that at least about 0.1% to at least about 10% of the total number of cells express PD-L1.
  • the PD-L1 positive or PD-L1 expression positive tumor means that at least about 1% of the total number of cells express PD-L1 on the cell surface.
  • the PD-L1 positive or PD-L1 expression positive tumor means that at least about 5% of the total number of cells express PD-L1 on the cell surface. In one particular aspect, PD-L1 positive or PD-L1 expression positive tumor means that at least about 1%, or in the range of 1- 5% of the total number of cells express PD-L1 on the cell surface.
  • the tumor samples are analyzed by a pathologist, a physician, or other qualified person such as a researcher, a laboratory technician, or a healthcare provider.
  • an automated method is used to analyze the tumor samples.
  • the tumor samples are further analyzed using any suitable algorithm, for example, a machine-learning algorithm.
  • the measuring PD-L1 (e.g., membranous PD-L1) expression can be achieved without obtaining a tumor sample.
  • a PD-L1 (e.g., membranous PD-L1) expression is measured by, for example, reviewing a report of test results from a laboratory.
  • the steps of the methods up to, and including, measuring a PD-L1 (e.g., membranous PD-L1) expression provides an intermediate or definitive result that may be provided to a physician or other healthcare provider for use in identifying a human subject suitable anticancertherapy or anti-cancer therapies (e.g., immunotherapy or chemotherapy) for treating cancer.
  • the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other aspects, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician.
  • the immunotherapy useful for the subject or a population of subjects afflicted with a solid THS tumor comprises a small molecule, an antibody, or any combination thereof.
  • the immunotherapy comprises a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, a LAG-3 antagonist, a TIM3 antagonist, a TIGIT antagonist, an NKG2a antagonist, an 0X40 antagonist, an ICOS antagonist, a MICA antagonist, a CD 137 antagonist, a KIR antagonist, a TGFP antagonist, an IL-10 antagonist, an IL-8 antagonist, a B7-H4 antagonist, a Fas ligand antagonist, a CXCR4 antagonist, a mesothelin antagonist, a CD27 antagonist, an GITR antagonist, or any combination thereof.
  • the PD-L1 inhibitor is a small molecule. In some aspects, the PD- L1 inhibitor comprises a millamolecule. In some aspects, the PD-L1 inhibitor comprises a macrocyclic peptide. In certain aspects, the PD-L1 inhibitor comprises BMS-986189.
  • the PD-L1 inhibitor comprises a millamolecule having a formula set forth in formula (I): wherein RkR 13 are amino acid side chains, R a -R n are hydrogen, methyl, or form a ring with a vicinal R group, and R 14 is -C(O)NHR 15 , wherein R 15 is hydrogen, or a glycine residue optionally substituted with additional glycine residues and/or tails which can improve pharmacokinetic properties.
  • the PD-L1 inhibitor comprises a compound disclosed in International Publication No. WO2014/151634.
  • the PD-L1 inhibitor comprises a compound disclosed in International Publication No.
  • WO2016/039749 WO2016/149351, WO2016/077518, W02016/100285, WO2016/100608, WO2016/126646, WO2016/057624, W02017/151830, WO20 17/176608, W02018/085750, WO2018/237153, or WO2019/070643.
  • the PD-L1 inhibitor comprises a small molecule PD-L1 inhibitor disclosed in International Publication No. WO2015/034820, WO2015/160641, WO2018/044963, WO20 17/066227, W02018/009505, WO2018/183171, WO2018/118848, WO2019/147662, or WO2019/169123.
  • the PD-L1 inhibitor comprises a combination of an anti-PD-Ll antibody disclosed herein and a PD-L1 small molecule inhibitor disclosed herein.
  • Anti-PD-1 antibodies that are known in the art can be used in the methods of the disclosure.
  • Various human monoclonal antibodies that bind specifically to PD-1 with high affinity have been disclosed in U.S. Patent No. 8,008,449.
  • the anti-PD-1 antibody comprises nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK-3475; see WO2008/156712), PDR001 (Novartis; see WO 2015/112900), MEDL0680 (AstraZeneca; also known as AMP-514; see WO 2012/145493), cemiplimab (Regeneron; also known as REGN-2810; see WO 2015/112800), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; see Si-Yang Liu et al., J.
  • nivolumab also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538
  • pembrolizumab Merck;
  • BGB-A317 Beigene; also known as Tislelizumab; see WO 2015/35606 and US 2015/0079109
  • INCSHR1210 Jiangsu Hengrui Medicine; also known as SHR-1210; see WO 2015/085847; Si-Yang Liu et al., J. Hematol. Oncol. 70:136 (2017)
  • TSR- 042 Tesaro Biopharmaceutical; also known as ANB011; see WO2014/179664)
  • GLS-010 Wangi/Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang Liu et al., J. Hematol.
  • the anti-PD-1 antibody is nivolumab.
  • Nivolumab is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9 846-56).
  • the anti-PD-1 antibody is pembrolizumab.
  • Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1).
  • S228P humanized monoclonal IgG4
  • Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.
  • Anti-PD-1 antibodies usable in the disclosed methods also include isolated antibodies that bind specifically to human PD-1 and cross-compete for binding to human PD-1 with any anti-PD-1 antibody disclosed herein, e.g., nivolumab (see, e.g., U.S. Patent No. 8,008,449 and 8,779,105; WO 2013/173223).
  • the anti-PD-1 antibody binds the same epitope as any of the anti-PD-1 antibodies described herein, e.g., nivolumab.
  • cross-competing antibodies are expected to have functional properties very similar those of the reference antibody, e.g., nivolumab, by virtue of their binding to the same epitope region of PD-1.
  • Cross-competing antibodies can be readily identified based on their ability to cross-compete with nivolumab in standard PD-1 binding assays such as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223).
  • the antibodies that cross-compete for binding to human PD-1 with, or bind to the same epitope region of human PD-1 antibody, nivolumab are monoclonal antibodies.
  • these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.
  • Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
  • Anti-PD-1 antibodies usable in the methods of the disclosed disclosure also include antigen-binding portions of the above antibodies. It has been amply demonstrated that the antigenbinding function of an antibody can be performed by fragments of a full-length antibody.
  • Anti-PD-1 antibodies suitable for use in the disclosed methods are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway.
  • an "anti-PD-1 antibody” includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits the functional properties similar to those of whole antibodies in inhibiting ligand binding and up-regulating the immune system.
  • the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.
  • the anti-PD-1 antibody is administered at a dose ranging from 0.1 mg/kg to 20.0 mg/kg body weight once every 2, 3, 4, 5, 6, 7, or 8 weeks, e.g., 0.1 mg/kg to 10.0 mg/kg body weight once every 2, 3, or 4 weeks. In other aspects, the anti-PD-1 antibody is administered at a dose of about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or 10 mg/kg body weight once every 2 weeks.
  • the anti-PD-1 antibody is administered at a dose of about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or 10 mg/kg body weight once every 3 weeks.
  • the anti-PD-1 antibody is administered at a dose of about 5 mg/kg body weight about once every 3 weeks.
  • the anti-PD-1 antibody e.g., nivolumab
  • the anti-PD-1 antibody e.g., pembrolizumab
  • the anti-PD-1 antibody useful for the present disclosure can be administered as a flat dose.
  • the anti-PD-1 antibody is administered at a flat dose of from about 100 to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 480 mg, or from about 240 mg to about 480 mg,
  • the anti-PD-1 antibody is administered as a flat dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about
  • the anti-PD-1 antibody is administered as a flat dose of about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg, at a dosing interval of about 1, 2, 3, or 4 weeks.
  • the anti-PD-1 antibody is administered as a flat dose of about 200 mg at about once every 3 weeks. In some aspects, the anti-PD-1 antibody is administered as a flat dose of about 400 mg at about once every 6 weeks. In other aspects, the anti-PD-1 antibody is administered as a flat dose of about 200 mg at about once every 2 weeks. In other aspects, the anti- PD-1 antibody is administered as a flat dose of about 240 mg at about once every 2 weeks. In other aspects, the anti-PD-1 antibody is administered as a flat dose of about 360 mg at about once every 3 weeks. In certain aspects, the anti-PD-1 antibody is administered as a flat dose of about 480 mg at about once every 4 weeks.
  • nivolumab is administered at a flat dose of about 240 mg once about every 2 weeks. In some aspects, nivolumab is administered at a flat dose of about 240 mg once about every 3 weeks. In some aspects, nivolumab is administered at a flat dose of about 360 mg once about every 3 weeks. In some aspects, nivolumab is administered at a flat dose of about 480 mg once about every 4 weeks.
  • pembrolizumab is administered at a flat dose of about 200 mg once about every 2 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 200 mg once about every 3 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 400 mg once about every 4 weeks.
  • the anti-PD-1 antibody e.g., nivolumab
  • the anti-PD-1 antibody, e.g., nivolumab is administered subcutaneously at a flat dose of about 600 mg once every two weeks.
  • the anti-PD-1 antibody, e.g., nivolumab is administered subcutaneously at a flat dose of about 1200 mg once every four weeks.
  • the PD-1 inhibitor is a small molecule. In some aspects, the PD-1 inhibitor comprises a millamolecule. In some aspects, the PD-1 inhibitor comprises a macrocyclic peptide. In certain aspects, the PD-1 inhibitor comprises BMS-986189. In some aspects, the PD-1 inhibitor comprises an inhibitor disclosed in International Publication No. WO2014/151634. In some aspects, the PD-1 inhibitor comprises INCMGA00012 (Insight Pharmaceuticals). In some aspects, the PD-1 inhibitor comprises a combination of an anti-PD-1 antibody disclosed herein and a PD-1 small molecule inhibitor.
  • an anti-PD-Ll antibody is substituted for an anti-PD-1 antibody in any of the methods or uses disclosed herein.
  • Anti-PD-Ll antibodies that are known in the art can be used in the methods of the present disclosure.
  • Examples of anti-PD-Ll antibodies useful in the methods of the present disclosure include the antibodies disclosed in US Patent No. 9,580,507.
  • 9,580,507 have been demonstrated to exhibit one or more of the following characteristics: (a) bind to human PD-L1 with a KD of 1 X 10' 7 M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) increase T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (c) increase interferon-y production in an MLR assay; (d) increase IL-2 secretion in an MLR assal(e) stimulate antibody responses; and (f) reverse the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • Anti-PD-Ll antibodies usable in the present disclosure include monoclonal antibodies that bind specifically to human PD-L1 and exhibit at least one, in some aspects, at least five, of the preceding characteristics.
  • the anti-PD-Ll antibody is selected from the group consisting of BMS-936559 (also known as 12A4, MDX-1105; see, e.g, U.S. Patent No. 7,943,743 and WO 2013/173223), atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see US 8,217,149; see, also, Herbst et al.
  • the PD-L1 antibody is atezolizumab (TECENTRIQ®).
  • Atezolizumab is a fully humanized IgGl monoclonal anti-PD-Ll antibody.
  • the PD-L1 antibody is durvalumab (IMFINZITM).
  • Durvalumab is a human IgGl kappa monoclonal anti-PD-Ll antibody.
  • the PD-L1 antibody is avelumab (BAVENCIO®).
  • Avelumab is a human IgGl lambda monoclonal anti-PD-Ll antibody.
  • Anti-PD-Ll antibodies usable in the disclosed methods also include isolated antibodies that bind specifically to human PD-L1 and cross-compete for binding to human PD-L1 with any anti-PD-Ll antibody disclosed herein, e.g., atezolizumab, durvalumab, and/or avelumab.
  • the anti-PD-Ll antibody binds the same epitope as any of the anti-PD-Ll antibodies described herein, e.g., atezolizumab, durvalumab, and/or avelumab.
  • antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region.
  • These cross-competing antibodies are expected to have functional properties very similar those of the reference antibody, e.g., atezolizumab and/or avelumab, by virtue of their binding to the same epitope region of PD-L1.
  • Cross-competing antibodies can be readily identified based on their ability to cross-compete with atezolizumab and/or avelumab in standard PD-L1 binding assays such as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223).
  • the antibodies that cross-compete for binding to human PD-L1 with, or bind to the same epitope region of human PD-L1 antibody as, atezolizumab, durvalumab, and/or avelumab are monoclonal antibodies.
  • these crosscompeting antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.
  • Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
  • Anti-PD-Ll antibodies usable in the methods of the disclosed disclosure also include antigen-binding portions of the above antibodies. It has been amply demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • Anti-PD-Ll antibodies suitable for use in the disclosed methods are antibodies that bind to PD-L1 with high specificity and affinity, block the binding of PD-1, and inhibit the immunosuppressive effect of the PD-1 signaling pathway.
  • an “anti-PD-Ll antibody” includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits the functional properties similar to those of whole antibodies in inhibiting receptor binding and up-regulating the immune system.
  • the anti-PD-Ll antibody or antigenbinding portion thereof cross-competes with atezolizumab, durvalumab, and/or avelumab for binding to human PD-L1.
  • the anti-PD-Ll antibody useful for the present disclosure can be any PD-L1 antibody that specifically binds to PD-L1, e.g., antibodies that cross-compete with durvalumab, avelumab, or atezolizumab for binding to human PD-1, e.g., an antibody that binds to the same epitope as durvalumab, avelumab, or atezolizumab.
  • the anti-PD-Ll antibody is durvalumab.
  • the anti-PD-Ll antibody is avelumab.
  • the anti- PD-Ll antibody is atezolizumab.
  • the anti-PD-Ll antibody is administered at a dose ranging from about 0.1 mg/kg to about 20.0 mg/kg body weight, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg, about once every 2, 3, 4, 5, 6, 7, or 8 weeks.
  • the anti-PD-Ll antibody is administered at a dose of about 15 mg/kg body weight at about once every 3 weeks. In other aspects, the anti-PD-Ll antibody is administered at a dose of about 10 mg/kg body weight at about once every 2 weeks.
  • the anti-PD-Ll antibody useful for the present disclosure is a flat dose.
  • the anti-PD-Ll antibody is administered as a flat dose of from about 200 mg to about 1600 mg, about 200 mg to about 1500 mg, about 200 mg to about 1400 mg, about 200 mg to about 1300 mg, about 200 mg to about 1200 mg, about 200 mg to about 1100 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 700 mg to about 1300 mg, about 800 mg to about 1200 mg, about 700 mg to about 900 mg, or about 1100 mg to about 1300 mg.
  • the anti-PD-Ll antibody is administered as a flat dose of at least about 240 mg, at least about 300 mg, at least about 320 mg, at least about 400 mg, at least about 480 mg, at least about 500 mg, at least about 560 mg, at least about 600 mg, at least about 640 mg, at least about 700 mg, at least 720 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 900 mg, at least 960 mg, at least about 1000 mg, at least about 1040 mg, at least about 1100 mg, at least about 1120 mg, at least about 1200 mg, at least about 1280 mg, at least about 1300 mg, at least about 1360 mg, or at least about 1400 mg, at a dosing interval of about 1, 2, 3, or 4 weeks.
  • the anti-PD-Ll antibody is administered as a flat dose of about 1200 mg at about once every 3 weeks. In other aspects, the anti-PD-Ll antibody is administered as a flat dose of about 800 mg at about once every 2 weeks. In other aspects, the anti-PD-Ll antibody is administered as a flat dose of about 840 mg at about once every 2 weeks.
  • Atezolizumab is administered as a flat dose of about 1200 mg once about every 3 weeks. In some aspects, atezolizumab is administered as a flat dose of about 800 mg once about every 2 weeks. In some aspects, atezolizumab is administered as a flat dose of about 840 mg once about every 2 weeks.
  • avelumab is administered as a flat dose of about 800 mg once about every 2 weeks.
  • durvalumab is administered at a dose of about 10 mg/kg once about every 2 weeks. In some aspects, durvalumab is administered as a flat dose of about 800 mg/kg once about every 2 weeks. In some aspects, durvalumab is administered as a flat dose of about 1200 mg/kg once about every 3 weeks.
  • the checkpoint inhibitor a disclosed herein comprises a CTLA-4 inhibitor.
  • the CTLA-4 inhibitor is an anti-CTLA-4 antibody.
  • Anti-CTLA-4 antibodies that are known in the art can be used in the methods of the present disclosure.
  • Anti-CTLA-4 antibodies of the instant disclosure bind to human CTLA-4 so as to disrupt the interaction of CTLA-4 with a human B7 receptor. Because the interaction of CTLA- 4 with B7 transduces a signal leading to inactivation of T-cells bearing the CTLA-4 receptor, disruption of the interaction effectively induces, enhances or prolongs the activation of such T cells, thereby inducing, enhancing or prolonging an immune response.
  • 6,984,720 have been demonstrated to exhibit one or more of the following characteristics: (a) binds specifically to human CTLA-4 with a binding affinity reflected by an equilibrium association constant (K a ) of at least about 10 7 M’ 1 , or about 10 9 M’ 1 , or about 10 10 M’ 1 to 10 11 M’ 1 or higher, as determined by Biacore analysis; (b) a kinetic association constant (k a ) of at least about 10 3 , about 10 4 , or about 10 5 nr 1 s’ 1 ; (c) a kinetic disassociation constant (kd) of at least about 10 3 , about 10 4 , or about 10 5 m’ 1 s’ 1 ; and (d) inhibits the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86).
  • Anti-CTLA-4 antibodies useful for the present disclosure include monoclonal antibodies that bind specifically to human CTLA-4 and exhibit at least one, at least two, or at least three of the preceding characteristics.
  • the CTLA-4 antibody is selected from the group consisting of ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Patent No. 6,984,720), MK- 1308 (Merck), AGEN-1884 (Agenus Inc.; see WO 2016/196237), and tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO 2000/037504 and Ribas, Update Cancer Ther. 2(3): 133-39 (2007)).
  • the anti-CTLA-4 antibody is ipilimumab.
  • the CTLA-4 antibody is ipilimumab for use in the methods disclosed herein.
  • Ipilimumab is a fully human, IgGl monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligands, thereby stimulating T cell activation and improving overall survival (OS) in patients with advanced melanoma.
  • the CTLA-4 antibody is tremelimumab.
  • the CTLA-4 antibody is MK-1308.
  • CTLA-4 antibody is AGEN-1884.
  • Anti-CTLA-4 antibodies usable in the disclosed methods also include isolated antibodies that bind specifically to human CTLA-4 and cross-compete for binding to human CTLA-4 with any anti-CTLA-4 antibody disclosed herein, e.g., ipilimumab and/or tremelimumab.
  • the anti-CTLA-4 antibody binds the same epitope as any of the anti-CTLA-4 antibodies described herein, e.g., ipilimumab and/or tremelimumab.
  • the ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region.
  • cross-competing antibodies are expected to have functional properties very similar those of the reference antibody, e.g., ipilimumab and/or tremelimumab, by virtue of their binding to the same epitope region of CTLA-4.
  • Cross-competing antibodies can be readily identified based on their ability to cross-compete with ipilimumab and/or tremelimumab in standard CTLA-4 binding assays such as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223).
  • the antibodies that cross-compete for binding to human CTLA-4 with, or bind to the same epitope region of human CTLA-4 antibody as, ipilimumab and/or tremelimumab are monoclonal antibodies.
  • these crosscompeting antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.
  • Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
  • Anti-CTLA-4 antibodies usable in the methods of the disclosed disclosure also include antigen-binding portions of the above antibodies. It has been amply demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • Anti-CTLA-4 antibodies suitable for use in the disclosed methods are antibodies that bind to CTLA-4 with high specificity and affinity, block the activity of CTLA-4, and disrupt the interaction of CTLA-4 with a human B7 receptor.
  • an anti-CTLA-4 "antibody” includes an antigen-binding portion or fragment that binds to CTLA-4 and exhibits the functional properties similar to those of whole antibodies in inhibiting the interaction of CTLA-4 with a human B7 receptor and up-regulating the immune system.
  • the anti-CTLA-4 antibody or antigen-binding portion thereof cross-competes with ipilimumab and/or tremelimumab for binding to human CTLA-4.
  • the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at a dose ranging from 0.1 mg/kg to 10.0 mg/kg body weight once every 2, 3, 4, 5, 6, 7, or 8 weeks. In some aspects, the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at a dose of 1 mg/kg or 3 mg/kg body weight once every 3, 4, 5, or 6 weeks. In one aspect, the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at a dose of 3 mg/kg body weight once every 2 weeks. In another aspect, the anti-PD-1 antibody or antigenbinding portion thereof is administered at a dose of 1 mg/kg body weight once every 6 weeks.
  • the anti-CTLA-4 antibody or antigen-binding portion thereof is administered as a flat dose.
  • the anti-CTLA-4 antibody is administered at a flat dose of from about 10 to about 1000 mg, from about 10 mg to about 900 mg, from about 10 mg to about 800 mg, from about 10 mg to about 700 mg, from about 10 mg to about 600 mg, from about 10 mg to about 500 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 100 mg, from about 100 mg to about 500 mg, from about 100 mg to about 480 mg, or from about 240 mg to about 480 mg.
  • the anti-CTLA-4 antibody or antigen-binding portion thereof is administered as a flat dose of at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about 520 mg at least about 540 mg, at least about 550 mg, at least about 560 mg, at least about 580 mg, at least about 600 mg, at least about 620 mg, at least about 640 mg, at least about 660 mg, at least about 680 mg, at least about 700 mg, or at least about
  • ipilimumab is administered at a dose of about 3 mg/kg once about every 3 weeks. In some aspects, ipilimumab is administered at a dose of about 10 mg/kg once about every 3 weeks. In some aspects, ipilimumab is administered at a dose of about 10 mg/kg once about every 12 weeks. In some aspects, the ipilimumab is administered for four doses.
  • LAG-3 antagonist includes, but is not limited to, LAG-3 binding agents, e.g., a LAG-3 antibody, and soluble LAG-3 polypeptides, e.g., a fusion protein comprising the extracellular portion of LAG-3.
  • LAG-3 binding agents e.g., a LAG-3 antibody
  • soluble LAG-3 polypeptides e.g., a fusion protein comprising the extracellular portion of LAG-3.
  • LAG-3 antagonist as used herein is interchangeable with the term "LAG-3 inhibitor.”
  • the LAG-3 antagonist is a soluble LAG-3 polypeptide.
  • the soluble LAG-3 polypeptide is a fusion polypeptide, e.g., a fusion protein comprising the extracellular portion of LAG-3.
  • the soluble LAG-3 polypeptide is a LAG-3- Fc fusion polypeptide capable of binding to MHC Class II.
  • the soluble LAG-3 polypeptide comprises a ligand binding fragment of the LAG-3 extracellular domain.
  • the soluble LAG-3 polypeptide further comprises a half-life extending moiety.
  • the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof.
  • the soluble LAG-3 polypeptide is IMP321 (eftilagimod alpha). See, e.g., Brignone C, et al., J. Immunol. (2007); 179:4202-4211 and W02009/044273.
  • the LAG-3 antagonist is an anti-LAG-3 antibody.
  • Anti-LAG-3 antibodies (or VH/VL domains derived therefrom) suitable for use herein can be generated using methods well known in the art. Alternatively, art recognized anti- LAG-3 antibodies can be used. Antibodies that bind to LAG-3 have been disclosed, for example, in Int'l Publ. No. WO/2015/042246 and U.S. Publ. Nos. 2014/0093511 and 2011/0150892.
  • An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. Publ. No. 2011/0150892).
  • An additional exemplary LAG-3 antibody useful in the present disclosure is BMS-986016 (relatlimab).
  • an anti -LAG-3 antibody useful in the present disclosure cross-competes with 25F7 or BMS-986016 (relatlimab) for binding to human LAG-3.
  • an anti -LAG-3 antibody useful in the present disclosure binds to the same epitope as 25F7 or BMS-986016 (relatlimab).
  • anti-LAG-3 antibodies that can be used in the methods and for the uses of the disclosure include IMP731 (H5L7BW) described in US 2011/007023, MK-4280 (28G-10) described in WO2016028672, REGN3767 (fianlimab) described in Burova E, et al., J. Immunother. Cancer (2016); 4(Supp.
  • anti-LAG-3 antibodies useful in the claimed invention can be found in, for example: US 10,188,730, WO 2016/028672, WO 2017/106129, WO2017/062888, W02009/044273, WO2018/069500, WO2016/126858, WO2014/179664, WO2016/200782, W02015/200119, WO2017/019846, WO2017/198741, WO2017/220555, WO2017/220569, WO20 18/071500, W02017/015560, WO2017/025498, WO2017/087589, WO2017/087901, W02018/083087, WO2017/149143, WO2017/219995, US2017/0260271, WO2017/086367, WO20 17/086419, WO2018/034227, WO2018/185046, WO2018/185043, WO2018/217940, W019/011306, WO2018/208868, W
  • Anti-LAG-3 antibodies that can be used in the methods and for the uses of the disclosure also include isolated antibodies that bind specifically to human LAG-3 and crosscompete for binding to human LAG-3 with any anti-LAG-3 antibody disclosed herein, e.g., relatlimab.
  • the anti-LAG-3 antibody binds the same epitope as any of the anti- LAG-3 antibodies described herein, e.g., relatlimab.
  • the antibodies that cross-compete for binding to human LAG-3 with, or bind to the same epitope region as, any anti-LAG-3 antibody disclosed herein, e.g., relatlimab are monoclonal antibodies.
  • these crosscompeting antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.
  • Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
  • cross-competing antibodies are expected to have functional properties very similar those of the reference antibody, e.g., relatlimab, by virtue of their binding to the same epitope region.
  • Cross-competing antibodies can be readily identified based on their ability to cross-compete in standard binding assays such as Biacore analysis, ELISA assays or flow cytometry see, e.g., WO 2013/173223).
  • Anti-LAG-3 antibodies that can be used in the methods and for the uses of the disclosure also include antigen-binding portions of any of the above full-length antibodies. It has been amply demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • Biosimilars of any of the anti-LAG-3 antibodies disclosed herein can also be used in the methods and for the uses of the disclosure.
  • the therapy useful for the disclosure includes a combination of an anti-PD-1 antibody, e.g., nivolumab, and an anti-LAG3 antibody, e.g, relatlimab.
  • the therapy for the disclosure includes a single composition comprising an anti-PD-1 antibody, e.g, nivolumab, and an anti-LAG3 antibody, e.g., relatlimab.
  • the anti-LAG-3 antibody has the heavy and light chain CDRs or variable regions of any of the anti-LAG-3 antibodies disclosed herein, e.g., relatlimab.
  • the antibody comprises CDR1, CDR2, and CDR3 domains of the VH region of an anti-LAG-3 antibody disclosed herein, e.g., relatlimab, and CDR1, CDR2 and CDR3 domains of the VL region of the antibody, e.g., relatlimab.
  • the anti-LAG-3 antibody comprises VH and/or VL regions of any of the anti-LAG-3 antibodies disclosed herein, e.g., relatlimab.
  • the anti-LAG-3 antibody is a full-length antibody.
  • the anti-LAG-3 antibody is a monoclonal, chimeric, humanized, human, or multispecific antibody.
  • the multispecific antibody is a dual-affinity retargeting antibody (DART), a DVD-Ig, or bispecific antibody.
  • the anti-LAG-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.
  • the anti-LAG-3 antibody is BMS-986016 (relatlimab), LAG-525 (IMP-701, ieramilimab), MK-4280 (28G-10), REGN3767 (fianlimab), TSR-033, TSR-075, Sym022, FS-118, IMP731 (H5L7BW), GSK2831781, humanized BAP050, aLAG3(0414), aLAG3(0416), XmAb22841, MGD013, BI754111, P 13B02-30, AVA-017, 25F7, AGEN1746, or comprises an antigen binding portion thereof
  • an anti-LAG-3 antibody is used to determine LAG-3 expression.
  • an anti-LAG-3 antibody is selected for its ability to bind to LAG-3 in formalin- fixed, paraffin-embedded (FFPE) tissue specimens.
  • FFPE paraffin-embedded
  • an anti-LAG-3 antibody is capable of binding to LAG-3 in frozen tissues.
  • an anti-LAG-3 antibody is capable of distinguishing membrane bound, cytoplasmic, and/or soluble forms of LAG-3.
  • an anti-LAG-3 antibody useful for assaying, detecting, and/or quantifying LAG-3 expression in accordance with the methods described herein is the 17B4 mouse IgGl anti-human LAG-3 monoclonal antibody, or an antigen binding fragment thereof. See, e.g., Matsuzaki, J et al., PNAS 107, 7875 (2010).
  • the immunotherapy disclosed herein comprises a TIM-3 inhibitor.
  • the TIM-3 inhibitor is an anti-TIM-3 antibody.
  • Anti-TIM-3 antibodies that are known in the art can be used in the presently described methods.
  • the anti-TIM-3 antibody is TSR-022, LY3321367, or an anti-TIM- 3 antibody disclosed in WO 2018/013818.
  • the anti-TIM-3 antibody binds specifically to human TIM-3 and cross-competes for binding to human TIM-3 with any anti-TIM-3 antibody disclosed herein. In some aspects, the anti-TIM-3 antibody binds the same epitope as any of the anti-TIM-3 antibodies described herein. In some aspects, the antibodies that cross-compete for binding to human TIM-3 with, or bind to the same epitope region as, any anti-TIM-3 antibody disclosed herein are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. [0270] Anti-TIM-3 antibodies that can be used in the methods and for the uses of the disclosure also include antigen-binding portions of any of the above full-length antibodies.
  • Biosimilars of any of the anti-TIM-3 antibodies disclosed herein can also be used in the methods and for the uses of the disclosure.
  • the anti-TIM-3 antibody has the heavy and light chain CDRs or variable regions of any of the anti-TIM-3 antibodies disclosed herein. Accordingly, in one aspect, the antibody comprises CDR1, CDR2, and CDR3 domains of the VH region of an anti-TIM-3 antibody disclosed herein, and CDR1, CDR2 and CDR3 domains of the VL region of the antibody. In another aspect, the anti-TIM-3 comprises VH and/or VL regions of any of the anti-TIM-3 antibodies disclosed herein.
  • the anti-TIM-3 antibody is a full-length antibody.
  • the anti-TIM-3 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody.
  • the multispecific antibody is a DART, a DVD-Ig, or bispecific antibody.
  • the anti-TIM-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.
  • the immunotherapy disclosed herein comprises an anti-OX40 (also known as CD 134, TNFRSF4, ACT35 and/or TXGP1L) antibody.
  • the anti-OX40 antibody comprises BMS-986178 (Bristol-Myers Squibb Company), described in Int'l Publ. No. WO20160196228.
  • the anti-OX40 antibody comprises selected from the anti- 0X40 antibodies described in Int'l Publ. Nos.
  • WO95012673 WO199942585, WO14148895, WO15153513, WO15153514, WO13038191, WO16057667, W003106498, WO12027328, WO13028231, W016200836, WO 17063162, WO17134292, WO 17096179, WO 17096281, and WO 17096182.
  • the immunotherapy comprises an anti-NKG2A antibody.
  • NKG2A is a member of the C-type lectin receptor family that is expressed on natural killer (NK) cells and a subset of T lymphocytes. Specifically, NKG2A primarily expressed on tumor infiltrating innate immune effector NK cells, as well as on some CD8+ T cells. Its natural ligand human leukocyte antigen E (HLA-E) is expressed on solid and hematologic tumors. NKG2A is an inhibitory receptor that blinds HLA-E.
  • NK natural killer
  • HLA-E human leukocyte antigen E
  • the anti-NKG2A antibody comprises BMS-986315, a human monoclonal antibody that blocks the interaction of NKG2A to its ligand HLA-E, thus allowing activation of an anti-tumor immune response.
  • the anti-NKG2A antibody comprises a checkpoint inhibitor that activates T cells, NK cells, and/or tumor-infiltrating immune cells.
  • the anti-NKG2A antibody comprises selected from the anti-NKG2A antibodies described in, for example, WO 2006/070286 (Innate Pharma S.A.; University of Genova); U.S. Patent No.
  • the immunotherapy comprises an anti-ICOS antibody.
  • ICOS is an immune checkpoint protein that is a member of the CD28-superfamily.
  • ICOS is a 55-60 kDa type I transmembrane protein that is expressed on T cells after T cell activation and co-stimulates T- cell activation after binding its ligand, ICOS-L (B7H2).
  • ICOS is also known as inducible T-cell co-stimulator, CVID1, AILIM, inducible costimulator, CD278, activation-inducible lymphocyte immunomediatory molecule, and CD278 antigen.
  • the anti-ICOS antibody comprises BMS-986226, a humanized IgG monoclonal antibody that binds to and stimulates human ICOS.
  • the anti- ICOS antibody comprises selected from anti-ICOS antibodies described in, for example, WO 2016/154177 (Jounce Therapeutics, Inc.), WO 2008/137915 (Medlmmune), WO 2012/131004 (INSERM, French National Institute of Health and Medical Research), EP3147297 (INSERM, French National Institute of Health and Medical Research), WO 2011/041613 (Memorial Sloan Kettering Cancer Center), EP 2482849 (Memorial Sloan Kettering Cancer Center), WO 1999/15553 (Robert Koch Institute), U.S.
  • Patent Nos. 7,259,247 and 7,722,872 Robot Kotch Institute
  • WO 1998/038216 Japanese Tobacco Inc.
  • US. Patents. Nos. 7,045,615; 7,112,655, and 8,389,690 Japan Tobacco Inc.
  • U.S. Patent Nos. 9,738,718 and 9,771,424 GaxoSmithKline
  • WO 2017/220988 Kymab Limited
  • the immunotherapy comprises an anti-TIGIT antibody.
  • the anti-TIGIT antibody comprises BMS-986207.
  • the anti-TIGIT antibody comprises clone 22G2, as described in WO 2016/106302.
  • the anti-TIGIT antibody comprises MTIG7192A/RG6058/RO7092284, or clone 4.1D3, as described in WO 2017/053748.
  • the anti-TIGIT antibody comprises selected from the anti-TIGIT antibodies described in, for example, WO 2016/106302 (Bristol-Myers Squibb Company) and WO 2017/053748 (Genentech).
  • the subject is administered a monotherapy, e.g., wherein the subject is administered a single therapeutic agent and is not administered one or more additional therapeutic agent (e.g., an anti-cancer agent).
  • the subject is administered a combination therapy, e.g., wherein the subject is administered first therapeutic agent and one or more additional therapeutic agent (e.g., an anti-cancer agent).
  • the monotherapy comprise an anti-cancer agent that is a checkpoint inhibitor.
  • the combination comprise a first anti-cancer agent and additional therapeutic agent that is a checkpoint inhibitor. In some aspects, the combination comprise a first anti-cancer agent that is a checkpoint inhibitor and additional therapeutic agent that is a checkpoint inhibitor.
  • the checkpoint inhibitor comprises a programmed death- 1 (PD-1) pathway inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B and T cell lymphocyte attenuator (BTLA) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA) inhibitor, an indoleamine 2,3 -dioxygenase (IDO) inhibitor, a nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitor, a killer-cell immunoglobulin- like receptor (KIR) inhibitor, an adenosine A2a receptor (A2aR) inhibitor
  • PD-1 cyto
  • the subject is administered a PD-1 monotherapy, e.g., wherein the subject is administered a single therapeutic agent and is not administered one or more additional therapeutic agent (e.g., an anti-cancer agent).
  • the subject is administered a PD-L1 monotherapy, e.g., wherein the subject is administered a single therapeutic agent and is not administered one or more additional therapeutic agent (e.g., an anti-cancer agent).
  • the subject is administered a combination therapy, e.g., wherein the subject is administered a PD-1 therapy and one or more additional therapeutic agent (e.g., an anti-cancer agent).
  • the subject is administered a combination therapy, e.g., wherein the subject is administered a PD-L1 therapy and one or more additional therapeutic agent (e.g., an anti-cancer agent).
  • the immunotherapy comprises administering to the human subject a PD-1 antagonist.
  • the PD-1 antagonist comprises a small molecule.
  • the small molecule comprises a macrocyclic peptide.
  • the macrocyclic peptide comprises BMS 986189.
  • the PD-1 antagonist comprises an anti-PD-1 antibody.
  • the anti-PD-1 antibody comprises an antibody comprising nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, or any combination thereof.
  • the anti-PD-1 antibody cross-competes with nivolumab or pembrolizumab for binding to human PD-1.
  • the anti-PD-1 antibody comprises nivolumab or pembrolizumab.
  • the immunotherapy comprises administering to the human subject a PD-L1 antagonist.
  • the PD-L1 antagonist comprises an anti PD-L1 antibody comprising BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301, ICO 36, or any combination thereof.
  • the anti PD-L1 antibody cross-competes with atezolizumab, avelumab or durvalumab for binding to human PD-L1.
  • the anti PD-L1 antibody comprises atezolizumab, avelumab or durvalumab.
  • the immunotherapy comprises administering to the human subject a combination therapy.
  • the combination therapy comprises administering to the human subject (i) an anti-PD-1 antibody or an anti-PD-Ll antibody and (ii) a second agent.
  • the second agent comprises a CTLA-4 antagonist, a LAG-3 antagonist, a TIM3 antagonist, a TIGIT antagonist, a TIM3 antagonist, a NKG2a antagonist, an 0X40 antagonist, an ICOS antagonist, a MICA antagonist, a CD137 antagonist, a KIR antagonist, a TGFp antagonist, an IL- 10 antagonist, an IL-8 antagonist, a B7-H4 antagonist, a Fas ligand antagonist, a CXCR4 antagonist, a mesothelin antagonist, a CD27 antagonist, a GITR antagonist, or any combination thereof.
  • the second agent comprises an antibody, such as, for example, an anti- CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti-TGFp antibody, an anti-IL-10 antibody, an anti-IL-8 antibody, an anti-B7-H4 antibody, an anti -Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD27 antibody, an anti-GITR, or any combination thereof.
  • an antibody such as, for example, an anti- CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA
  • the second agent comprises a CTLA-4 antibody.
  • the combination therapy comprises an anti-PD-1 antibody and an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody cross-competes with ipilimumab or tremelimumab for binding to human CTLA-4.
  • the combination therapy comprises an anti-PD-1 antibody and ipilimumab or tremelimumab.
  • the combination therapy comprises nivolumab and ipilimumab.
  • the combination therapy comprises nivolumab tremelimumab.
  • the combination therapy comprises an anti-PD-1 antibody and a LAG-3 antagonist.
  • the LAG-3 antagonist is an anti-LAG-3 antibody.
  • the combination therapy comprises an anti-PD-1 antibody and an anti-LAG-3 antibody.
  • the anti-LAG-3 antibody cross-competes with BMS-986016 (relatlimab), LAG-525 (IMP- 701, ieramilimab), MK-4280 (28G-10), REGN3767 (fianlimab), TSR-033, TSR-075, Sym022, FS- 118, IMP731 (H5L7BW), GSK2831781, humanized BAP050, aLAG3(0414), aLAG3(0416), XmAb22841, MGD013, BI754111, P 13B02-30, AVA-017, 25F7, or AGEN1746, for binding to human LAG-3.
  • the anti -LAG-3 antibody comprises BMS-986016 (relatlimab), LAG-525 (IMP-701, ieramilimab), MK-4280 (28G-10), REGN3767 (fianlimab), TSR-033, TSR- 075, Sym022, FS-118, IMP731 (H5L7BW), GSK2831781, humanized BAP050, aLAG3(0414), aLAG3(0416), XmAb22841, MGD013, BI754111, P 13B02-30, AVA-017, 25F7, AGEN1746, or comprises an antigen binding portion thereof.
  • the combination therapy comprises an anti-PD-1 antibody and relatlimab.
  • the combination therapy comprises nivolumab and relatlimab.
  • the LAG-3 antagonist is a soluble LAG-3 polypeptide.
  • the soluble LAG-3 polypeptide comprises a ligand binding fragment of the LAG-3 extracellular domain.
  • the soluble LAG-3 polypeptide further comprises a half-life extending moiety, comprising, for example, an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof.
  • the LAG-3 antagonist comprises IMP321 (eftilagimod alpha).
  • the combination therapy comprises an anti-PD-1 antibody and IMP321 (eftilagimod alpha).
  • the chemotherapeutic agent useful for the subject or a population of subjects afflicted with an ascinar THS tumor comprises an alkylating agent, an antimetabolite, an antineoplastic antibiotic, a mitotic inhibitor, a hormone or hormone modulator, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, other neoplastic agent, or any combination thereof.
  • Non-limiting examples alkylating agents include, but are not limited to, 5 -azacytidine, decitabine, temozolomide, dactinomycin (or actinomycin-D), melphalan, altretamine, carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, streptozocin, thiotepa, oxaliplatin, trabectedin, or any combination thereof.
  • Nonlimiting examples of antimetabolite include, but are not limited to, azacitidine, 6-mercaptopurine, capecitabine (Xeloda), clofarabine, gemcitabine (or Gemzar), nelarabine, claribine, 5 -fluorouracil, thioguanine (or 6-thioguanine), cytarabine (or arabinosylcytosine (Ara-C)), cytarabine liposomal (or Liposomal Ara-C, or DEPOCYTTM), decitabine (or DACOGEN®), hydroxyurea, fludarabine, floxuridine, cladribine (or 2-chlorodeoxyadenosine (2-CdA)), methotrexate (or amethopterin, or methotrexate sodium (MTX)), pemetrexed (or Alimta), pralatrexate, trifluridine/tipiracil, pentostatin, or any
  • Non-limiting examples of antineoplastic antibiotics include, but are not limited to, daunorubicin, doxorubicin (Adriamycin), doxorubicin liposomal, epirubicin, idarubicin, valrubicin, bleomycin, dactinomycin, mitomycin-C, mitoxantrone (also acts as a topoisomerase II inhibitor), or any combination thereof.
  • Non-limiting examples of mitotic inhibitors include, but are not limited to, eribulin, docetaxel, paclitaxel, vincristine, teniposide, etoposide, vinblastine, vinorelbine, cabazitaxel, ixabepilone, estramustine, or any combination thereof.
  • Non-limiting examples of hormones or hormone modulators include, but are not limited to, prednisone, methylprednisolone, dexamethasone, or any combination thereof.
  • Non-limiting examples of tyrosine kinase inhibitor include, but are not limited to, sorafenib (e.g., sorafenib tosylate, also known as NEXAVAR®), lenvatinib (e.g., lenvatinib mesylate, also known as LENVIMA®), regorafenib (e.g., STIVARGA®), cabozantinib (e.g., cabozantinib S-malate, also known as CABOMETYX®), sunitinib (e.g., sunitinib malate, also known as SUTENT®), brivanib, linifanib, erlotinib (e.g., erlotinib hydrocholoride, also known as TARCEVA®), pemigatinib (also known as PEMAZYRETM), everolimus (also known as AFINITOR® or ZORTRESS®), gefit
  • Non-limiting examples of epidermal growth factor inhibitor include, but are not limited to, tagrisso (osimertinib), tarceva (erlotinib), erbitux (cetuximab), iressa (gefitinib), gilotrif (afatinib), vectibix (panutumamab), or any combination thereof.
  • Non-limiting examples of proteasome inhibitor include, but are not limited to, velcade (bortezomib), krypolis (carfilzomib), ninlaro (ixazomib), delanzomib, or any combination thereof.
  • Non-limiting examples of other neoplastic agent include, but are not limited to, all-trans-retinoic acid, arsenic trioxide, asparaginase, eribulin, hydroxyurea, ixabepilone, mitotane, omacetaxine, pegaspargase, procarbazine, romidepsin, vorinostat, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (e.g., triplatin tetranitrate), lipoplatin, phenanthriplatin, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises an alkylating agent.
  • the alkylating agent comprises altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises a taxane.
  • the taxane comprises paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises a nucleoside analog.
  • the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises an antimetabolite.
  • the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises a topoisomerase inhibitor.
  • the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises an anthracycline.
  • the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.
  • the chemotherapy useful for treating an ascinar tumor comprises a vinca alkaloid.
  • the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol,ieridine, vinburnine, or any combination thereof.
  • the chemotherapy useful for the ascinar tumor comprises gemcitabine and cisplatin. In some aspects, the chemotherapy useful for the ascinar tumor comprises gemcitabine and carboplatin. In some aspects, the chemotherapy useful for the ascinar tumor comprises pemetrexed and cisplatin. In some aspects, the chemotherapy useful for the ascinar tumor comprises pemetrexed and carboplatin. In some aspects, the chemotherapy useful for the ascinar tumor comprises paclitaxel and carboplatin.
  • the chemotherapy useful for the ascinar tumor comprises gemcitabine, cisplatin, carboplatin, premetrexed, paclitaxel, or any combination thereof.
  • the methods of the disclosure further comprise administering to the subject an additional therapeutic agent and/or anti-cancer therapy.
  • the additional anti-cancer therapy can comprise any therapy known in the art for the treatment of a tumor in a subject and/or any standard-of-care therapy, as disclosed herein.
  • the additional anti-cancer therapy comprises a surgery, a radiation therapy, a chemotherapy, an immunotherapy, or any combination thereof.
  • the additional anti-cancer therapy comprises a chemotherapy, including any chemotherapeutic agent disclosed herein.
  • the chemotherapy comprises platinum-doublet chemotherapy.
  • the additional therapeutic agent comprises an anti-cancer agent.
  • the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent (e.g., a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topisomerase inhibitor, an anthracycline, a vinca alkaloid), an immunotherapeutic agent, , or any combination thereof.
  • chemotherapeutic agent e.g., a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topisomerase inhibitor, an anthracycline, a vinca alkaloid
  • the anti-angiogenesis agent comprises an inhibitor of a vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase with Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-MET), C- type lectin family 14 member A (CLEC14A), multimerin 2 (MMRN2), shock protein 70-1A (HSP70-1 A), a epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof.
  • VEGF vascular endothelial growth factor
  • VGF VEGF receptor
  • PDGF platelet-derived growth factor
  • PDGFR PDGF receptor
  • Ang angiopoietin
  • Ang tyrosine kinase with Ig-
  • the anti-angiogenesis agent comprises bevacizumab (also known as AVASTIN®), ramucirumab (also known as CYRAMZA®), aflibercept (also known as EYLEA® or ZALTRAP®), tanibirumab, olaratumab (also known as LARTRUVOTM), nesvacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.
  • the checkpoint stimulator comprises an agonist of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, inducible T cell co-stimulator (ICOS), ICOS-L, 0X40, OX40L, CD70, CD27, CD40, death receptor 3 (DR3), CD28H, or any combination thereof.
  • the immunotherapeutic agent comprises an antibody that specifically ICOS, CD137 (4-1BB), CD134 (0X40), NKG2A, CD27, CD96, GITR, Herpes Virus Entry Mediator (HVEM), PD-1, PD-L1, CTLA-4, BTLA, TIM-3, A2aR, Killer cell Lectin-like Receptor G1 (KLRG-1), Natural Killer Cell Receptor 2B4 (CD244), CD 160, TIGIT, VISTA, KIR, TGFP, IL-10, IL-8, B7-H4, Fas ligand, CSF1R, CXCR4, mesothelin, CEACAM-1, CD52, HER2, MICA, MICB, or any combination thereof.
  • the therapeutic agent that can be combined with an immunotherapy or a chemotherapy comprises a therapeutic agent that inhibits one or more of TGFb, KRAS, hedgehog, and notch signalling pathways.
  • a chemotherapy is administered in combination with an agent that inhibits one or more of TGFb, KRAS, hedgehog, and notch signalling pathways to a subject with an ascinar THS tumor.
  • the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (e.g., triplatin tetranitrate), lipoplatin, phenanthriplatin, or any combination thereof.
  • the alkylating agent comprises altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, or any combination thereof.
  • the taxane comprises paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, or any combination thereof.
  • the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.
  • the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.
  • the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.
  • the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.
  • the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol,êtdine, vinburnine, or any combination thereof.
  • the methods disclosed herein comprise administering to the human subject an anti-cancer therapy (e.g., immunotherapy or chemotherapy). In some aspects, the methods disclosed herein comprise administering to the human subject an immunotherapy.
  • an anti-cancer therapy e.g., immunotherapy or chemotherapy.
  • the methods disclosed herein comprise administering to the human subject an immunotherapy.
  • the anti-cancer therapy (e.g., immunotherapy or chemotherapy) is administered at a weight-based dose.
  • the anti-cancer therapy e.g., immunotherapy or chemotherapy
  • the anti-cancer therapy (e.g., immunotherapy or chemotherapy) is formulated for intravenous administration.
  • the anti-cancer therapy (e.g., immunotherapy or chemotherapy) is formulated for subcutaneous administration.
  • the anti-cancer therapy is an immunotherapy.
  • the immunotherapy is a monotherapy.
  • the immunotherapy is a combination therapy.
  • the first and the second anti-cancer treatment in a combination therapy are formulated separately. In some aspects, the first and the second anti-cancer treatment in a combination therapy are formulated together (z.e., as a single composition).
  • two or more anti-cancer treatment in a combination therapy are formulated separately. In some aspects, two or more anti-cancer treatment in a combination therapy are formulated together.
  • two or more anti-cancer treatment in a combination therapy are administered concurrently.
  • an anti-cancer therapy (e.g., immunotherapy or chemotherapy) is administered at a dose from about 0.0001 to about 100 mg/kg or about 0.01 to about 5 mg/kg of the subject's body weight.
  • doses can be about 0.3 mg kg body weight, about 1 mg/kg body weight, about 3 mg/kg body weight, about 5 mg/kg body weight or about 10 mg/kg body weight or within the range of about 1 to about 10 mg/kg.
  • anti-cancer treatment is administered once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
  • an anti-cancer therapy e.g., immunotherapy or chemotherapy
  • an anti-cancer therapy (e.g., immunotherapy or chemotherapy) is administered at a dose of about 1, about 3, about 10, about 20, about 50, about 80, about 100, about 120, about 130, about 150, about 160, about 180, about 200, about 240 or about 280 mg, about 320, about 360, about 400, about 440, about 480 mg, about 520, about 560, about 600, about 640, about 680, about 720, about 760, about 800, about 840, about 880, about 920, about 960, about 1000 mg, about 1040, about 1080, about 1120, about 1160, about 1200, about 1240, about 1280, about 1320, about 1360, about 1400, about 1440, about 1480, about 1520, about 1560, about 1600, about 1640, about 1680, about 1720, about 1760, about 1800, about 1840, about 1880, about 1920, about 1960, or about 2000 mg.
  • an anti-cancer therapy e.g., immunotherapy or chemotherapy
  • the anti-cancer therapy is an immunotherapy.
  • the immunotherapy comprises one or more antibodies.
  • the antibody is an anti-PD-1 antibody.
  • the anti- PD-1 antibody is nivolumab and is administered at a flat dose of about 240 mg once about every 2 weeks.
  • nivolumab is administered at a flat dose of about 240 mg once about every 3 weeks.
  • nivolumab is administered at a flat dose of about 360 mg once about every 3 weeks.
  • nivolumab is administered at a flat dose of about 480 mg once about every 4 weeks.
  • the antibody is pembrolizumab and is administered at a flat dose of about 200 mg once about every 2 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 200 mg once about every 3 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 400 mg once about every 4 weeks.
  • the antibody is atezolizumab and is administered as a flat dose of about 800 mg once about every 2 weeks. In some aspects, atezolizumab is administered as a flat dose of about 840 mg once about every 2 weeks.
  • the antibody is durvalumab and is administered at a dose of about 10 mg/kg once about every 2 weeks. In some aspects, durvalumab is administered as a flat dose of about 800 mg/kg once about every 2 weeks. In some aspects, durvalumab is administered as a flat dose of about 1200 mg/kg once about every 3 weeks.
  • the antibody is avelumab and is administered as a flat dose of about 800 mg once about every 2 weeks.
  • the antibody is ipilimumab and is administered at a dose of at least about 3 mg/kg once about every 3 weeks. In some aspects, ipilimumab is administered at a dose of at least about 10 mg/kg once about every 3 weeks. In some aspects, ipilimumab is administered at a dose of at least about 10 mg/kg once about every 12 weeks. In some aspects, the ipilimumab is administered for four doses. II.H. Outcomes
  • Patients treated according to the methods disclosed herein can experience improvement in at least one sign of cancer.
  • improvement is measured by a reduction in the quantity and/or size of measurable tumor lesions.
  • lesions can be measured on chest x-rays or CT or MRI films.
  • cytology or histology can be used to evaluate responsiveness to a therapy.
  • the patient treated exhibits a complete response (CR), a partial response (PR), stable disease (SD), immune-related complete disease (irCR), immune-related partial response (irPR), or immune-related stable disease (irSD).
  • CR complete response
  • PR partial response
  • SD stable disease
  • irCR immune-related complete disease
  • irPR immune-related partial response
  • irSD immune-related stable disease
  • the patient treated experiences tumor shrinkage and/or decrease in growth rate, z.e., suppression of tumor growth.
  • unwanted cell proliferation is reduced or inhibited.
  • one or more of the following can occur: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited; recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent.
  • the methods provided herein produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions appearing over time, complete remission, partial remission, or stable disease.
  • the median duration of response is > 3 month, > 6 month, > 12 month, or > 18 month.
  • the median duration of response is > 6 month.
  • the frequency of patients with duration of response > 6 month is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or about 100%.
  • the median duration of response is > 3 month, > 6 month, > 12 month, or > 18 month. In one aspect, the median duration of response is > 6 month.
  • the frequency of patients with duration of response > 6 month is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99% or 100%.
  • the subject exhibits improved overall survival or progression free survival compared to a subject who does not have a solid THS.
  • the administering treats the cancer.
  • the administering reduces the size of a tumor associated with the cancer.
  • the size of the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the administration.
  • the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration.
  • the subject exhibits stable disease after the administration.
  • the subject exhibits a partial response after the administration.
  • the subject exhibits a complete response after the administration.
  • kits comprising means to perform the methods as disclosed herein.
  • Kits typically include a label indicating the intended use of the contents of the kit and instructions for use.
  • the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • this disclosure provides a kit identifying a human subject afflicted with a tumor of a non-small cell lung cancer suitable for an anti-cancer therapy (e.g., immunotherapy or chemotherapy), the kit comprising: (a) means for processing a tumor sample (e.g., a fixative, a storage medium, and/or a embedding medium, (b) means for staining the tumor sample (e.g., reagents for performing Hematoxylin and Eosin staining), (c) means for mounting the tumor sample for microscopy analysis (e.g., a mounting medium), (d) instructions for determining the tumor sample THS according to the methods disclosed herein.
  • the kit may further comprise (a) means for measuring a tumor sample PD-L1 expressions (e.g
  • kits means for measuring a tumor sample TIS (e.g., regents and components to perform an RNA-Seq).
  • TIS tumor sample
  • the kit may further comprise instruction for analyzing the measured PD-L1 expression, TMB or TIS.
  • the kit may further comprise positive and negative controls, such as a control sample expressing PD-L1, a control sample having a defined TMB, a control sample having a defined TIS.
  • the kit further comprises an anticancer treatment to be administered in an anti-cancer therapy (e.g., immunotherapy or chemotherapy).
  • an anticancer therapy e.g., immunotherapy or chemotherapy.
  • the kit may comprise a PD-1 pathway inhibitor.
  • the kit comprises a dosage the PD-1 pathway inhibitor, including any of the doses for checkpoint inhibitors disclosed herein.
  • the PD-1 pathway inhibitor is an anti-human PD-1 antibody disclosed herein, e.g., nivolumab or pembrolizumab, and/or an anti-PD-Ll antibody disclosed herein, e.g., atezolizumab, durvalumab, or avelumab.
  • the kit comprises a dosage of an anti-PD-1 antibody and/or an anti-PD-Ll antibody.
  • the kit further comprises a CTLA-4 antagonist, a LAG3 antagonist, and/or an anti-TIM-3 antagonist, as described herein.
  • Example 1 Correlation between Response and Tumor Histologic Subtype (THS)
  • STUDY II Part 1 was a single arm, Phase 2 study investigating Nivolumab (3 mg/kg Q2W)+Ipilimumab (1 mg/kg Q6W) in advanced/metastatic NSCLC patients with PD-L1 expression 0-100%.
  • STUDY III was a randomized Phase 3 study investigating Nivolumab monotherapy (3 mg/kg Q3W) versus investigator’s choice Chemotherapy in advanced/metastatic NSCLC.
  • STUDY IV was a randomized Phase 3 study investigating Nivolumab (360 mg Q3W) + Ipilimumab (1 mg/kg Q6W) + Chemotherapy (NSQ: pemetrexed + cisplatin or carboplatin; SQ: paclitaxel + carboplatin) Q3W (2 cycles) versus Chemotherapy (NSQ: pemetrexed + cistplatin or carboplatin; SQ: paclitaxel + carboplatin) Q3W (4 cycles) in advanced/metastatic NSCLC. Both treatment arms in this study involved treatment with Chemotherapy.
  • Table 1 STUDY I patients' baseline patient characteristics
  • WHO World Health Organization
  • Pathologists annotated histologic pattern as either, solid, acinar and others (e.g., lepidic, cribiform, micropapillary, papillary and not otherwise specified) based on the predominant subtype, defined as presence of >50% of a particular pattern. In the event discordance was found among the three pathologists then the consensus (2/3) governed.
  • Kaplan Meier curves were plotted for overall survival (OS) or progression free survival (PFS) stratified by tumor histologic subtype for each respective study. Median survival rates and Cox proportional hazards ratios were calculated for each tumor hystological subtype in each treatment arm.
  • Tumor hystological subtype assessment is an elegant approach to identify patients with improved/reduced efficacy to an anti-cancer therapy (e.g., immunotherapy or chemotherapy), based on a single H&E slide that is typically available for most NSCLC patients at the time of diagnosis.
  • Assessment of tumor hystological subtype not only captures the pathological features of the tumor microenvironment, but also captures multiple biological features known to be associated with efficacy to anti-cancer therapies (e.g., immunotherapy or chemotherapy).
  • Tumor PD-L1 expression was evaluated using pre-treatment, archived samples from patients enrolled to each clinical study using an immunohistochemical assay with monoclonal rabbit anti-PD-Ll (clone 28-8) antibody (Dako 28-8 pharmDx assay, Agilent Technologies).
  • PD-L1 expression (0-100%) was evaluated based on a minimum of 100 tumor cells on each slide.
  • Tumor mutational burden was evaluated for STUDY I, STUDY II, STUDY III, and STUDY IV using a next-generation sequencing based test that uses targeted high throughput hybridization-based capture technology for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) (FoundationOne®CDx, Foundation Medicine).
  • MSI microsatellite instability
  • TMB tumor mutational burden
  • STUDY III TMB was evaluated using whole exome sequencing. Gene expression profiling was performed in STUDY III and STUDY I using RNAseq data derived from archived, pre-treatment tumor samples.
  • TMB tumor mutational burden
  • TPS tumor proportion score
  • MsigDB molecular sigantures database
  • Tumors with solid histology were also associated with higher inflammation and proliferation signatures, and higher T cell expression.
  • Several pro-inflammatory chemoattractant cytokines were upregulated in solid tumors, including CXCL9, CXCL19, CXCL11 and CXCL13 (Fig. 2C).
  • Genes associated with inflammation such as, for example, IFNg, IFNa, JAK/STAT were found to be more highly expressed in tumors with solid histology, compared to acinar.
  • Proliferation related genes such as, E2F targets, G2M checkpoints, and mitotic spindle related genes, as well as KIR2DL4, which is expressed on subsets of T cells, were also found to be highly expressed in solid vs acinar tumors.
  • tumors with acinar histology showed higher expression of hallmark gene sets representative of certain pathways, including, for example, KRAS, notch, hedgehog, TGFb, and angiogenesis pathways (Fig. 2D).
  • inhibitors of these genes or pathways such as, e.g., TGFb pathway inhibitors, angiogenesis pathway inhibitors (e.g., VEGFR inhibitors) may provide clinical benefit in patients with acinar tumors.
  • the work presented herein is the first demonstration that solid and acinar tumor hystological subtypes are associated with PD-L1, TMB and inflammation in non-squamous NSCLC and are associated with response to immunotherapy and chemotherapy-based regimens. This information may inform treatment decisions and outcomes expectations in patients treated with immunotherapy or chemotherapy.

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Abstract

L'invention concerne un procédé d'identification ou de traitement d'un sujet humain atteint d'une tumeur d'un cancer du poumon non à petites cellules non squameux approprié pour une thérapie anticancéreuse (par exemple, une immunothérapie ou une chimiothérapie), comprenant l'évaluation d'un sous-type histologique de tumeur (THS) de la tumeur, et le traitement du sujet avec une thérapie anticancéreuse (par exemple, une immunothérapie ou une chimiothérapie).
PCT/US2024/020580 2023-03-20 2024-03-19 Évaluation de sous-type de tumeur pour une thérapie anticancéreuse WO2024196952A1 (fr)

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