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Immuno-Oncology: Identification of Therapeutic Targets, Development of Novel Drugs and Improvement of Treatment Approaches for Cancer

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 36540

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Special Issue Editor

Dr. Veronica Balatti

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Research Scientist, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
Interests: cancer genetics; small noncoding RNAs dysregulation in cancer; gene expression dysregulation in cancer; targeted therapy for cancer; chronic lymphocytic leukemia; lung cancer

Special Issue Information

Dear Colleagues

Recently, we witnessed an extraordinary development in cancer therapy, led by the evolving field of immuno–oncology. Traditional chemotherapy destroys cancer cells, but it also affects healthy cells. To overcome this dilemma, researchers have tried several approaches. Hormonal therapies inhibit growth-promoting hormones or block their survival signal to cancer cells, but this strategy only works for certain cancer types derived from hormonally responsive tissues. Thus, compounds targeting cancer-specific mutated genes were generated, and more target molecules are currently being investigated to develop new drugs. Immunotherapy is an evolution of targeted therapy where the immune system is targeted to improve its ability to kill cancer cells. Passive immunotherapies enhance the immune system’s antitumor response using monoclonal antibodies, and the aim of current research is to optimize this strategy by developing personalized treatments. Active immunotherapy directly stimulates the immune system to kill cancer cells either by targeting immune-checkpoints inhibitors (thus interfering with the tumor’s ability to inhibit the immune system from attacking cancer cells) or by engineering patient T cells to recognize and kill cancer cells more efficiently (CAR-T therapy). Additionally, effective vaccines are already employed for infectious agent-related cancers and immunoprevention of cancers not related to infectious agents was observed in transgenic mice with activated oncogenes, indicating that stimulation of the immune system in healthy hosts can inhibit carcinogenesis. These strategies, are having an extraordinary success, but they can have side effects. Since these approaches are quickly taking over classic chemotherapy, perfecting immuno–oncology is essential to improve patient wellbeing. Hence, in this issue, we will discuss the most recent discoveries leading to the development of a new generation of drugs and therapeutic approaches for cancer treatment.

Dr. Veronica Balatti
Guest Editor

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Keywords

Cancer treatments
Molecular genetics of cancer
Targeted therapy
Immunotherapy
Monoclonal antibody therapy
Cytokine therapy
Checkpoint inhibitors
CAR-T cells
Combination therapy
Cancer immunoprevention

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Published Papers (6 papers)

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Review

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25 pages, 647 KiB

Open AccessReview

A Holistic Perspective: Exosomes Shuttle between Nerves and Immune Cells in the Tumor Microenvironment

by Mihnea P. Dragomir, Vlad Moisoiu, Roxana Manaila, Barbara Pardini, Erik Knutsen, Simone Anfossi, Moran Amit and George A. Calin

J. Clin. Med. 2020, 9(11), 3529; https://doi.org/10.3390/jcm9113529 - 31 Oct 2020

Cited by 10 | Viewed by 3397

Abstract

One of the limitations of cancer research has been the restricted focus on tumor cells and the omission of other non-malignant cells that are constitutive elements of this systemic disease. Current research is focused on the bidirectional communication between tumor cells and other components of the tumor microenvironment (TME), such as immune and endothelial cells, and nerves. A major success of this bidirectional approach has been the development of immunotherapy. Recently, a more complex landscape involving a multi-lateral communication between the non-malignant components of the TME started to emerge. A prime example is the interplay between immune and endothelial cells, which led to the approval of anti-vascular endothelial growth factor-therapy combined with immune checkpoint inhibitors and classical chemotherapy in non-small cell lung cancer. Hence, a paradigm shift approach is to characterize the crosstalk between different non-malignant components of the TME and understand their role in tumorigenesis. In this perspective, we discuss the interplay between nerves and immune cells within the TME. In particular, we focus on exosomes and microRNAs as a systemic, rapid and dynamic communication channel between tumor cells, nerves and immune cells contributing to cancer progression. Finally, we discuss how combinatorial therapies blocking this tumorigenic cross-talk could lead to improved outcomes for cancer patients. Full article

(This article belongs to the Special Issue Immuno-Oncology: Identification of Therapeutic Targets, Development of Novel Drugs and Improvement of Treatment Approaches for Cancer)

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57 pages, 1376 KiB

Open AccessReview

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

by Anne M. Macpherson, Simon C. Barry, Carmela Ricciardelli and Martin K. Oehler

J. Clin. Med. 2020, 9(9), 2967; https://doi.org/10.3390/jcm9092967 - 14 Sep 2020

Cited by 28 | Viewed by 5120

Abstract

Recent advances in the understanding of immune function and the interactions with tumour cells have led to the development of various cancer immunotherapies and strategies for specific cancer types. However, despite some stunning successes with some malignancies such as melanomas and lung cancer, most patients receive little or no benefit from immunotherapy, which has been attributed to the tumour microenvironment and immune evasion. Although the US Food and Drug Administration have approved immunotherapies for some cancers, to date, only the anti-angiogenic antibody bevacizumab is approved for the treatment of epithelial ovarian cancer. Immunotherapeutic strategies for ovarian cancer are still under development and being tested in numerous clinical trials. A detailed understanding of the interactions between cancer and the immune system is vital for optimisation of immunotherapies either alone or when combined with chemotherapy and other therapies. This article, in two main parts, provides an overview of: (1) components of the normal immune system and current knowledge regarding tumour immunology, biology and their interactions; (2) strategies, and targets, together with challenges and potential innovative approaches for cancer immunotherapy, with attention given to epithelial ovarian cancer. Full article

(This article belongs to the Special Issue Immuno-Oncology: Identification of Therapeutic Targets, Development of Novel Drugs and Improvement of Treatment Approaches for Cancer)

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Figure 1

Figure 1
T-cell receptor (TCR) complex composed of α and β chains for antigen recognition, associated noncoavalently with CD3γε and CD3δε heterodimers, and a CD3ζ (CD247) homodimer. V, C = variable, constant immunoglobulin-like extracellular domains. i = ITAM (immune receptor tyrosine-based activation motif). Full article ">Figure 2
General structures of some common cancer immunotherapeutic agents or components. (a) IgG mAb. Fab = antigen binding fragment, Fc = complement and Fc receptor binding fragment. (b) Single chain variable fragment (scFv) structure, derived from the heavy and light chains of the variable antigen binding domain of a mAb. (The VL and VH units may be engineered in either order). (c) Tandem scFv, bispecific T-cell engager (BiTE) structure. C = constant region, V = variable region, H = heavy chain, L = light chain. Full article ">Figure 3
Chimeric antigen receptor (CAR) designs. Target binding in all generations has mostly used a scFv, linked via a hinge domain (mostly derived from IgG CH1CH2 or CH2CH3 regions) to a transmembrane region (mostly from CD3ξ) and a cytoplasmic region for TCR signaling from CD3ξ. The second generation added an intracellular costimulatory domain, and the third generation added two costimulatory domains. The costimulatory domains were usually CD28, CD137 (4-1BB/TNFRSF9), or CD134 (OX40). The fourth generation (TRUCKs) are engineered to release an inducible payload, usually IL-12, and may also contain a controllable on-off switch, or suicide gene. i = ITAM (immune receptor tyrosine-based activation motif). Full article ">

29 pages, 944 KiB

Open AccessReview

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

by Felice Pepe and Veronica Balatti

J. Clin. Med. 2020, 9(2), 593; https://doi.org/10.3390/jcm9020593 - 21 Feb 2020

Cited by 15 | Viewed by 5040

Abstract

In the past decade, novel targeted therapy approaches, such as BTK inhibitors and Bcl2 blockers, and innovative treatments that regulate the immune response against cancer cells, such as monoclonal antibodies, CAR-T cell therapy, and immunomodulatory molecules, have been established to provide support for the treatment of patients. However, drug resistance development and relapse are still major challenges in CLL treatment. Several studies revealed that non-coding RNAs have a main role in the development and progression of CLL. Specifically, microRNAs (miRs) and tRNA-derived small-RNAs (tsRNAs) were shown to be outstanding biomarkers that can be used to diagnose and monitor the disease and to possibly anticipate drug resistance and relapse, thus supporting physicians in the selection of treatment regimens tailored to the patient needs. In this review, we will summarize the most recent discoveries in the field of targeted therapy and immunotherapy for CLL and discuss the role of ncRNAs in the development of novel drugs and combination regimens for CLL patients. Full article

(This article belongs to the Special Issue Immuno-Oncology: Identification of Therapeutic Targets, Development of Novel Drugs and Improvement of Treatment Approaches for Cancer)

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19 pages, 834 KiB

Open AccessReview

Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer

by Daniel Sur, Andrei Havasi, Calin Cainap, Gabriel Samasca, Claudia Burz, Ovidiu Balacescu, Iulia Lupan, Diana Deleanu and Alexandru Irimie

J. Clin. Med. 2020, 9(1), 182; https://doi.org/10.3390/jcm9010182 - 9 Jan 2020

Cited by 49 | Viewed by 12383

Abstract

Chimeric antigen receptor (CAR) T-cell therapy represents a new genetically engineered method of immunotherapy for cancer. The patient’s T-cells are modified to express a specific receptor that sticks to the tumor antigen. This modified cell is then reintroduced into the patient’s body to fight the resilient cancer cells. After exhibiting positive results in hematological malignancies, this therapy is being proposed for solid tumors like colorectal cancer. The clinical data of CAR T-cell therapy in colorectal cancer is rather scarce. In this review, we summarize the current state of knowledge, challenges, and future perspectives of CAR T-cell therapy in colorectal cancer. A total of 22 articles were included in this review. Eligible studies were selected and reviewed by two researchers from 49 articles found on Pubmed, Web of Science, and clinicaltrials.gov. This therapy, at the moment, provides modest benefits in solid tumors. Not taking into consideration the high manufacturing and retail prices, there are still limitations like increased toxicities, relapses, and unfavorable tumor microenvironment for CAR T-cell therapy in colorectal cancer. Full article

(This article belongs to the Special Issue Immuno-Oncology: Identification of Therapeutic Targets, Development of Novel Drugs and Improvement of Treatment Approaches for Cancer)

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20 pages, 1392 KiB

Open AccessReview

Targeting of the Cancer-Associated Fibroblast—T-Cell Axis in Solid Malignancies

by Tom J. Harryvan, Els M. E. Verdegaal, James C. H. Hardwick, Lukas J. A. C. Hawinkels and Sjoerd H. van der Burg

J. Clin. Med. 2019, 8(11), 1989; https://doi.org/10.3390/jcm8111989 - 15 Nov 2019

Cited by 47 | Viewed by 6690

Abstract

The introduction of a wide range of immunotherapies in clinical practice has revolutionized the treatment of cancer in the last decade. The majority of these therapeutic modalities are centered on reinvigorating a tumor-reactive cytotoxic T-cell response. While impressive clinical successes are obtained, the majority of cancer patients still fail to show a clinical response, despite the fact that their tumors express antigens that can be recognized by the immune system. This is due to a series of other cellular actors, present in or attracted towards the tumor microenvironment, including regulatory T-cells, myeloid-derived suppressor cells and cancer-associated fibroblasts (CAFs). As the main cellular constituent of the tumor-associated stroma, CAFs form a heterogeneous group of cells which can drive cancer cell invasion but can also impair the migration and activation of T-cells through direct and indirect mechanisms. This singles CAFs out as an important next target for further optimization of T-cell based immunotherapies. Here, we review the recent literature on the role of CAFs in orchestrating T-cell activation and migration within the tumor microenvironment and discuss potential avenues for targeting the interactions between fibroblasts and T-cells. Full article

(This article belongs to the Special Issue Immuno-Oncology: Identification of Therapeutic Targets, Development of Novel Drugs and Improvement of Treatment Approaches for Cancer)

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Figure 1
Fibroblast heterogeneity in the tumor-microenvironment. (A–E). The origin of CAFs in the TME is diverse and they can be either derived from the activation of resident fibroblasts (A), endothelial-to-mesenchymal transition (EndoMT) (B), epithelial-to-mesenchymal transition (EMT) (C) bone-marrow derived mesenchymal cells (D) and/or other differential pathways (e.g., smooth muscle cell trans-differentiation (E)). (F,G). The function of these CAFs is diverse (F) and regulated by cues derived from within the TME, leading to formation of subsets with specific functions, including but not limited to, iCAFs (G). TGF-β, transforming growth factor β; ECM, extracellular matrix; CAF, cancer-associated fibroblast; iCAF, inflammatory CAF. Full article ">Figure 2
Therapeutic targeting of CAFs to enhance T-cell based immunotherapies. (A) Direct CAF targeting relies on the identification of CAF-selective targets to reduce ‘on-target off-CAF’ toxicity. RNA-sequencing based approaches enable identification of markers to target specific immunomodulatory CAF subsets. (B) Indirect CAF targeting relies on targeting of CAF-derived factors involved in T-cell exclusion and suppression. This can be done either through inhibiting CAF-derived cytokines involved in suppressing T-cell function (top-left), modulation of the ECM (top-right) or blocking of inhibitory chemotactic signals (e.g., TGF-β signaling) to improve accessibility of T-cells to the tumor (bottom-right) and/or inhibition of checkpoint molecules on CAFs or associated immune cells to potentiate tumoricidal T-cell effector functions (bottom-left). CAR, chimeric antigen receptor; FAP, fibroblast activation protein; CAF, cancer-associated fibroblast; iCAF, inflammatory CAF; IL-6, interleukin-6; ECM, extracellular matrix; TGF-β, transforming growth factor β. Full article ">

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11 pages, 911 KiB

Open AccessBrief Report

The Antitumor Effect of Heparin is not Mediated by Direct NK Cell Activation

by Gustavo R. Rossi, Jenifer P. Gonçalves, Timothy McCulloch, Rebecca B. Delconte, Robert J. Hennessy, Nicholas D. Huntington, Edvaldo S. Trindade and Fernando Souza-Fonseca-Guimaraes

J. Clin. Med. 2020, 9(8), 2666; https://doi.org/10.3390/jcm9082666 - 18 Aug 2020

Cited by 9 | Viewed by 3293

Abstract

Natural killer (NK) cells are innate lymphocytes responsible for the elimination of infected or transformed cells. The activation or inhibition of NK cells is determined by the balance of target cell ligand recognition by stimulatory and inhibitory receptors on their surface. Previous reports have suggested that the glycosaminoglycan heparin is a ligand for the natural cytotoxicity receptors NKp30, NKp44 (human), and NKp46 (both human and mouse). However, the effects of heparin on NK cell homeostasis and function remain unclear. Here, we show that heparin does not enhance NK cell proliferation or killing through NK cell activation. Alternatively, in mice models, heparin promoted NK cell survival in vitro and controlled B16-F10 melanoma metastasis development in vivo. In human NK cells, heparin promisingly increased interferon (IFN)-γ production in synergy with IL-12, although the mechanism remains elusive. Our data showed that heparin is not able to increase NK cell cytotoxicity. Full article

(This article belongs to the Special Issue Immuno-Oncology: Identification of Therapeutic Targets, Development of Novel Drugs and Improvement of Treatment Approaches for Cancer)

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Figure 1
Heparin reduced the number of melanoma lung metastases. (A) C57BL/6 mice were injected intravenously with 2 × 105 B16-F10 melanoma cells and treated with heparin (10 mg/kg every 2 days, subcutaneously), starting 1 day after tumor inoculation. After 15 days, mice were euthanized, and lung metastases were macroscopically counted. Graph is representative of two independent experiments. (B) Rag2−/−γc−/− recipients were injected intravenously with 1 × 105 B16-F10, inoculated with 4 × 105 sorted WT or Ncr1−/−(NKp46-deficient NK cells) 12 h later, and treated with heparin as in A. An unpaired t-test was used to compare differences between groups, where * p < 0.05 was used to compare to control. Full article ">Figure 2
Heparin stimulates murine NK cells survival, but not proliferation in vitro. NK cells were stained with CellTrace violet (CTV) and plated in 96-well plates in the presence of 50 ng/mL rIL-15 and 100 µg/mL heparin and evaluated by flow cytometry every 24 h. The number of divisions (A), and total cohort (B) were analyzed. Data of three technical replicates of one representative independent experiment out of three. Data are presented as mean ± SEM. Two-way ANOVA was used to compare differences between groups, where * p < 0.05 was considered for statistical significance. Full article ">Figure 3
Heparin does not increase the killing capacity of NK cells. (A,B) NK cells isolated from C57BL/6 mice were cultured in the presence of 20 ng/mL of rIL-15 and heparin (10 or 100 µg/mL). After 24 h, NK cells were incubated for 4 h with previously Calcein AM-stained B16-F10 (A) or YAC-1 cells (B). Killing quantification was determined by the intensity of fluorescence in the supernatant and compared to control of each experiment. Each symbol in the scatterplots represents the average of three biological replicates (presented as mean ± SEM). Two-way ANOVA was used to compare differences between groups. (C) NK cells isolated from human peripheral blood mononuclear cells were cultured in the presence of rIL-15 (50 ng/mL), with or without heparin (1 or 100 µg/mL). After 24 h, NK cells were labeled with CTV and co-cultured with A375 cells (ratio 4:1—NK:A375 cell). After 4 h, cells were stained with Annexin V-Fluorescein isothiocyanate (FITC) and propidium iodide and evaluated by flow cytometry. Dead tumor cells were considered CTV-, Annexin V+, and/or PI+. Each point represents technical replicates from two independent experiments (represented by full and empty symbols; presented as mean ± SEM). An unpaired t-test was used to compare differences between groups, with p < 0.05. Full article ">Figure 4
Heparin further increases IL-12-mediated IFN-γ production by human NK cells. NK cells isolated from umbilical cord blood were cultured in the presence of rIL-15 (50 ng/mL) and rIL-18 (50 ng/mL), with or without heparin (1 or 100 µg/mL) or rIL-12 (10 pg/mL) for 24 h. The supernatant was collected and IFN-γ quantified by ELISA. Each point represents technical replicates from two independent experiments (represented by full and empty symbols; presented as mean ± SEM). An unpaired t-test was used to compare differences between groups, where * p < 0.05 was used to compare to control. Full article ">

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