383 results about "Immune checkpoint" patented technology

This invention relates generally to bifunctional molecules including (a) a TGFβRII or fragment thereof capable of binding TGFβ and (b) an antibody, or antigen binding fragment thereof, that binds to an immune checkpoint protein, such as Programmed Death Ligand 1 (PD-L1), uses of such molecules (e.g., for treating cancer), and methods of making such molecules.

The present invention relates to methods for developing engineered T-cells for immunotherapy and more specifically to methods for modifying T-cells by inactivating at immune checkpoint genes, preferably at least two selected from different pathways, to increase T-cell immune activity. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to highly efficient adoptive immunotherapy strategies for treating cancer and viral infections.

This invention relates generally to bifunctional molecules including (a) a TGFβRII or fragment thereof capable of binding TGFβ and (b) an antibody, or antigen binding fragment thereof, that binds to an immune checkpoint protein, such as Programmed Death Ligand 1 (PD-L1), uses of such molecules (e.g., for treating cancer), and methods of making such molecules.

Provided herein are methods of modulating and redirecting an immune response. Compositions and methods for killing targeted cells in a cell population are also provided wherein, a cell population containing target cells expressing a target associated antigen and T cells are contacted with 1, 2, or more immune checkpoint antagonists and a multispecific T cell-redirecting agent that specifically binds the target associated antigen expressed on the target cells and specifically binds a T cell surface antigen.

The present invention is directed to selected anti-PD-1 antibodies capable of binding to both cynomolgus monkey PD-1 and to human PD-1: PD-1 mAb 1, PD-1 mAb 2, PD-1 mAb 3, PD-1 mAb 4, PD-1 mAb 5, PD-1 mAb 6, PD-1 mAb 7, PD-1 mAb 8, PD-1 mAb 9, PD-1 mAb 10, PD-1 mAb 11, PD-1 mAb 12, PD-1 mAb 13, PD-1 mAb 14, or PD-1 mAb 15, and to humanized and chimeric versions of such antibodies. The invention additionally pertains to PD-1-binding molecules that comprise PD-1 binding fragments of such anti-PD-1 antibodies, immunocongugates, and to bispecific molecules, including diabodies, BiTEs, bispecific antibodies, etc., that comprise (i) such PD-1-binding fragments, and (ii) a domain capable of binding an epitope of a molecule involved in regulating an immune check point present on the surface of an immune cells. The present invention also pertains to methods of using molecules that bind PD-1 for stimulating immune responses, as well as methods of detecting PD-1.

A method is disclosed for decreasing or retarding an increase in the size of a localized or metastatic tumor by using a combination of an immune stimulating cytotoxic gene therapy and immune-checkpoint modulating agent, in conjunction with other therapies, including radiation therapy, chemotherapy, surgery, and immunotherapies.

The present invention provides an oncolytic virus comprising nucleotide sequence(s) encoding one or more immune checkpoint modulator(s). It also concerns a pharmaceutical composition comprising effective amount of said oncolytic virus and, eventually, a pharmaceutically acceptable vehicle and its use for treating proliferative diseases such as cancers.

The present invention relates to methods for developing engineered T-cells for immunotherapy that are non-alloreactive. The present invention relates to methods for modifying T-cells by inactivating both genes encoding T-cell receptor and an immune checkpoint gene to unleash the potential of the immune response. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to standard and affordable adoptive immunotherapy strategies for treating cancer and viral infections.

The present invention relates to combination therapies comprising at least one activator of Tie-2 and immunotherapies that target immune checkpoints. Combination therapies of the disclosure can provide therapeutic effects not obtained with singly-administered immunotherapies. Combination therapies can be used to increase the therapeutic efficacy of an immunotherapy, to provide lower dosages of an immunotherapy being administered, to lower a toxicity of an immunotherapy, or to manage a side effect of an immunotherapy.

The present invention provides a combination comprising at least an oncolytic virus and one or more immune checkpoint modulator(s) for use for the treatment of a proliferative disease such as cancer. It also relates to a kit comprising said oncolytic virus and said one or more immune checkpoint modulator(s) in separate containers. It also concerns a pharmaceutical composition comprising effective amount of said oncolytic virus and said one or more immune checkpoint modulator(s).

The invention is directed to a method of predicting clinical response of a patient to treatment of a cancer by an immune checkpoint pathway inhibitor, such as an anti-CTLA-4 or anti-PD-1 antibody binding compound. In one aspect the method comprises generating pre- and post-treatment clonotype profiles, determining a number of clonotypes that decrease in frequency between the first and second clonotype profiles, and predicting a lack of responsiveness in the patient to the treatment whenever the number of clonotypes that decrease in frequency is greater than a predetermined value.

The invention relates to, among others, a method for assessing a prognosis of a patient with a malignant disease and / or for predicting the response of a patient with a malignant disease to immunotherapy. For this purpose, a DNA methylation analysis is carried out on at least one immunoregulatory gene of cells of the malignant disease and / or T lymphocytes which interact with the cells of the malignant disease, said gene coding for an immune checkpoint selected from B7 proteins and the receptors thereof, MHC-peptide complex-binding co-receptors, the members of the tumor necrosis factor receptorsuperfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18, and CD27, the members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2, BTNL2, and CD48, and the andenosine-binding adenosine 2A receptor.

The present invention relates to combination therapies comprising at least one activator of Tie-2 and immunotherapies that target immune checkpoints. Combination therapies of the disclosure can provide therapeutic effects not obtained with singly-administered immunotherapies. Combination therapies can be used to increase the therapeutic efficacy of an immunotherapy, to provide lower dosages of an immunotherapy being administered, to lower a toxicity of an immunotherapy, or to manage a side effect of an immunotherapy.

The present invention relates to the role of the microbiota in the efficacy of cancer treatments with a drug blocking an. immune checkpoint and provides methods and probiotics to improve the efficacy of such a treatment in patients in need thereof. More particularly, the invention pertains to the use of vancomycin or penicillin to modulate the gut microbiota to potentiate the anticancer effects of anti-CTLA4 molecules. B. fragilis or fecal microbial transplantation of a defined composition enriched in immunogenic Bacteroides spp. can also be used as a probiotic to that aim.

Compounds and pharmaceutical compositions that down-regulate immune checkpoints such as PD-1, PD-L1 and CTLA-4 are provided. Also provided are methods of treating a disease by down-regulating immune checkpoints such as PD-1, PD-L1 and CTLA-4. The methods are useful for treating cancer and viral infection in a subject.

Based on a CRISPR system, the invention provides sgRNAs specifically targeting to a human LAG-3 gene and a method for specifically knocking out the LAG-3 gene in human cells. The sgRNAs provided by the invention can accurately and effectively target to the human LAG-3 gene and precisely knock out the gene, and has excellent characteristics of high efficiency, short period and low cost. The methodcan be used for preparing human T cells having LAG-3 immune checkpoints knocked out, and then the human T cells are used in for tumor immunotherapy.

The invention provides an oncolytic virus construction body, an oncolytic virus and application thereof. The oncolytic virus construction body comprises a first nucleic acid molecule and a second nucleic acid molecule, wherein the first nucleic acid molecule encodes a secreted fusion protein molecule; the secreted fusion protein molecule is used for inhibiting immune checkpoints; and the second nucleic acid molecule encodes an immunostimulant molecule. According to the embodiment of the invention, the construction body encodes fusion protein and immunostimulant molecules for inhibiting the immune checkpoints and can inhibit immunosuppression mechanism mediated by the immune checkpoints and immunoreactions which causes individual tumor specificity so as to realize generalized and effectivetumor cell killing.

Use of a CXCR4 antagonistic peptide and an immune-check point regulator in the treatment of cancer is provided. Accordingly there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide having an amino acid sequence as set forth in SEQ ID NO: 1 or an analog or derivative thereof; and a therapeutically effective amount of a PD1 antagonist, a PDL-1 antagonist, a CTLA-4 antagonist, a LAG-3 antagonist, a TIM-3 antagonist, a KIR antagonist, an IDO antagonist, an OX40 agonist, a CD137 agonist, a CD27 agonist, a CD40 agonist, a GITR agonist, a CD28 agonist or an ICOS agonist, thereby treating the cancer in the subject. Also provided are pharmaceutical compositions and articles of manufacture.

Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors. Therapeutic blockade of these receptors has clinical efficacy in the treatment of cancer. While co-inhibitory receptors are co-expressed, the triggers that induce them and the transcriptional regulators that drive their co-expression have not been identified. The immunoregulatory cytokine IL-27 induces a gene module in T cells that includes several known co-inhibitory receptors (Tim-3, Lag-3, and TIGIT). The present invention provides a novel immunoregulatory network as well as novel cell surface molecules that have an inhibitory function in the tumor microenvironment. The present invention further provides the novel discovery that the transcription factors Prdm1 and c-Maf cooperatively regulate the expression of the co-inhibitory receptor module. This critical molecular circuit underlies the co-expression of co-inhibitory receptors in dysfunctional T cells and identifies novel regulators of T cell dysfunction.

The invention discloses a novel replicating oncolytic adenovirus capable of simultaneously inhibiting immune checkpoints of PD-L1 and TIGIT and application thereof. According to the novel replicatingoncolytic adenovirus capable of simultaneously inhibiting immune checkpoints of PD-L1 and TIGIT, a soluble fusion protein capable of simultaneously inhibiting immune checkpoints of PD-L1 and TIGIT andactivating immune costimulatory pathways is characterized in that both ends of the soluble fusion protein are a PD1 (programmed cell death protein 1) extracellular region for binding PD-L1 and a PVR(poliovirus receptor) extracellular region for binding TIGIT respectively, PD1 fragments and PVR fragments are connected through a linker sequence, and both ends of the soluble fusion protein can simultaneously inhibiting the immune checkpoints of PD-L1 and TIGIT after binding PD-L1 and TIGIT respectively. Experiments show that the novel replicating oncolytic adenovirus (ad5sPD1PVR) can significantly inhibit the immune checkpoints and activate antitumor immunity effects, achieve significant antitumor activity and accordingly have a good prospect and high values for developing antitumor drugs.

The invention provides a CAR-T cell capable of efficiently and stably expressing an inhibiting antibody and application thereof. Specifically, the invention provides a transgenic T cell, and the genome of the transgenic T cell is stably integrated with expression cassettes containing nucleic acid sequences coding chimeric antigen receptors and immune checkpoint inhibiting antibodies, wherein two ends of the expression cassettes contain inverted terminal repeats of transposons. In the genome of the pluripotent CAR-T cell, the expression cassettes of the inhibiting antibodies are stably integrated via a transposon system, so the CAR-T cell has the activity of stably and efficiently expressing the inhibiting antibodies on the premise that original killing activity of the T cell is maintained, transfer-back CAR-T cells are prevented from inhibition by a tumor microenvironment, and residual tumor-specific T cells can be activated in situ. Meanwhile, a molecular brake system is introduced to ensure the security of CAR-T cell therapy, and transfer-back pluripotent CAR-T cells can be timely removed if necessary.

The invention discloses a preparation method and application of a newcastle disease oncolytic virus expressing PD-L1 single chain antibody and an application thereof. The amino acid residues at sits of 112-117 of F protein of mutant recombinant LaSota strain newcastle disease virus is mutated into 112-R-R-Q-R-F-117, so that the newcastle disease oncolytic virus has independent infection capability; a PD-L1 single chain antibody gene is inserted between a P gene and M gene of a full-length clone of the newcastle disease virus LaSota strain through homologous recombination to obtain a finally modified full-length clone pBRN-FL (112-RRQRRF-117)-PDL1(ScFV); the recombinant virus is purified by chick embryo proliferation and ultracentrifugation. The rNDV-LaSota (112-RRQRRF-117)-PDL1(ScFV) recombinant virus has safety comparable to that of a LaSota original strain, and also has tumor killing capability and immune checkpoint inhibition function of a virulent strain.

Blockade of immune checkpoints such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) shows promise in patients with cancer. Inhibitory antibodies directed at these receptors have been shown to break immune tolerance and promote anti-tumor immunity. These agents work particularly well in patients with a certain category of tumor. Such tumors may be particularly susceptible to treatment because of the multitude of neoantigens which they produce.

The invention provides a unicell detection method for a tumor sample by means of a mass spectrum flow system. The method comprises the following steps that (1) a cancer tissue biopsy sample or blood sample of a tumor patient is collected and processed to prepare a unicell suspension; (2) an antibody labeled with metal elements is used to mark the suspended unicell suspension with multiple targetsat the same time; (3) the marked unicell sample is detected by the mass spectrum flow system; and (4) on the basis of obtained mass spectrum flow type detection data, different immunocyte subgroups are clustered and analyzed, and expression levels of protein in tumor immunization detection points in different subgroup cells are quantitatively analyzed. Thus, the immucyte subgroups that can reflectthe clinical response degree of tumor immunotherapy can be accurately found in the immunocyte cells related to tumor of high heteroplasmy, the protein expression level threshold of the tumour immunization detection pointd can be determined appropriately, and a detection result is high in clinical correlation. Thus, the method has good clinical application prospects and higher social benefit.

The invention relates to a fusion protein for restoring functions of debilitating immune cells. The fusion protein comprises a functional zone for identifying exhaustion immune cells and a functional zone for activating and amplifying the exhaustion immune cells. The two functional zones are connected through a non-functional amino acid fragment. According to the identification functional zone, an immune checkpoint specific antibody is utilized for identifying a phenotypic receptor of the exhaustion immune cells. According to the activation and amplification functional zone, cytokine or functional analogy mutant, or a ligand of surface receptor or functional analogy mutant, or an activated antibody is adopted for activation of the exhaustion immune cells. The invention also relates to application of the fusion protein. Tests show that the prepared fusion protein can identify exhaustion immune cells and also can activate and amplify the identified immune cells, restore the immune cells' function of killing antigen positive cells and enhance the functions of inhibiting tumor growth and controlling virus infection, and has a good clinical prospect and a wide application range.

Use of a CXCR4 antagonistic peptide and an immune-check point regulator in the treatment of cancer is provided. Accordingly there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide having an amino acid sequence as set forth in SEQ ID NO: 1 or an analog or derivative thereof; and a therapeutically effective amount of a PD1 antagonist, a PDL-1 antagonist, a CTLA-4 antagonist, a LAG-3 antagonist, a TIM-3 antagonist, a KIR antagonist, an IDO antagonist, an OX40 agonist, a CD137 agonist, a CD27 agonist, a CD40 agonist, a GITR agonist, a CD28 agonist or an ICOS agonist, thereby treating the cancer in the subject. Also provided are pharmaceutical compositions and articles of manufacture.

Compounds and pharmaceutical compositions that down-regulate immune checkpoints such as PD-1, PD-L1 and CTLA-4 are provided. Also provided are methods of treating a disease by down-regulating immune checkpoints such as PD-1, PD-L1 and CTLA-4. The methods are useful for treating cancer and viral infection in a subject.

The invention provides a gene combination and application thereof in preparation of a reagent for predicting prognosis of a patient treated with an immune checkpoint inhibitor. Based on the combination of 55 genes, the invention develops a tumor mutation score TMS32055 method through the gene combination, and TMS is defined as the number of genes containing non-synonymous mutations in a specific gene combination. TMS 55 is divided into 3 groups: TMS 55 is equal to 0, TMS 55 is greater than or equal to 1 and is less than or equal to 5, and TMS 55 is greater than 5. Compared with a group that TMS 55 is equal to 0, the patients of groups that TMS 55 is greater than or equal to 1 and is less than or equal to 5 and TMS 55 is greater than 5 have better prognosis and longer overall survival time.The TMS55 based on the 55-gene combination has higher prediction efficiency than TMB in predicting the overall survival after immunotherapy, and has uniform cutoff value. Therefore, the TMS55 can beused for predicting the prognosis of patients receiving immune checkpoint inhibition treatment, and is easier to popularize and apply in clinical practice.

The invention provides a multi-immunohistochemical analysis kit of lung cancer, and a using method and application thereof, and relates to the field of the multi-immunohistochemical technology. The multi-immunohistochemical analysis kit defines that the monoclonal antibody group comprises more than two types of a CD163 monoclonal antibody, a CD68 monoclonal antibody, a PDL1 monoclonal antibody, aCD8 monoclonal antibody, a PD1 monoclonal antibody and a CD57 monoclonal antibody. The multi-immunohistochemical analysis kit uses the human or animal in vitro tissue, which is given the immune checkpoint inhibitor, as the sample to test, so as to judge the lung cancer effect validity of the multi-immunohistochemical analysis kit. The invention further provides a using method of the multi-immunohistochemical analysis kit; the method can effectively mark not less than 6 types of immune checkpoints on the same one tissue; and the cross reaction does not exist among multiple marks.