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Special Issue "Targeting Immune Checkpoints and Immunotherapy"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 November 2017)

Special Issue Information

Dear Colleagues,

We are at the very beginning of a golden age in oncology. A major turning point in cancer immunotherapy came with the clinical application of antibodies that block immune checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1). We envision more clinical studies coming forth and opening a new chapter on the treatment paradigm.

This Special Issue aims to update this important area. It is a platform for cancer investigators to update the most current clinical studies, investigational targets, and further mechanistic understanding of the therapy.

Original research and full review articles are welcomed to submit to this special issue.

Scope of the Special Issue as below but not exclusive:

  • CAR T-cell immunotherapy for cancer
  • Clinical trials on the cancer immunotherapy
  • Immunotherapy, safety, side effects and drug resistance
  • Combination of immunotherapy, radiotherapy and chemotherapy
  • Neoantigen exposure and radiotherapy
  • Detection assays for immune checkpoints
  • Immuno-oncology treatment options
  • Novel immune checkpoint targets for cancer immunotherapy
  • Neoantigens signature
  • Vaccines and vaccination

Dr. William Chi-shing Cho
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

 

Published Papers (7 papers)

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Research

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Open AccessArticle Expansion of T Cells with Interleukin-21 for Adoptive Immunotherapy of Murine Mammary Carcinoma
Int. J. Mol. Sci. 2017, 18(2), 270; https://doi.org/10.3390/ijms18020270
Received: 25 November 2016 / Revised: 13 January 2017 / Accepted: 23 January 2017 / Published: 29 January 2017
Cited by 1 | PDF Full-text (2914 KB) | HTML Full-text | XML Full-text
Abstract
We previously demonstrated that culturing antigen-sensitized draining lymph node (DLN) lymphocytes from BALB/c mice in interleukin (IL)-7/15 after activation with bryostatin/ionomycin (B/I) is superior to culture in IL-2 for expansion, differentiation to cluster of differentiation (CD)8+ cells and anti-tumor activity. We sought to
[...] Read more.
We previously demonstrated that culturing antigen-sensitized draining lymph node (DLN) lymphocytes from BALB/c mice in interleukin (IL)-7/15 after activation with bryostatin/ionomycin (B/I) is superior to culture in IL-2 for expansion, differentiation to cluster of differentiation (CD)8+ cells and anti-tumor activity. We sought to determine whether the substitution or addition of IL-21 to culture had a similar effect. DLN lymphocytes were antigen-sensitized with 4T1 mammary carcinoma 10 days prior to harvest, activated with B/I, and expanded in culture for 7 days with either IL-2, IL-21, IL-2/21, IL-7/15, or IL-7/15/21. Cellular expansion, phenotype, interferon (IFN)-γ responses, and in vivo anti-tumor activity were compared. We found that T cells grown in IL7/15/21 demonstrated significantly greater lymphocyte expansion than IL-2, IL-21, IL-2/21, and IL-7/15 (38.4-fold vs. 5.5, 6.6, 9.5, and 23.9-fold, respectively). Of these expanded cells, IL-7/15/21 significantly expanded the greatest percentage of CD8+ cells (67.1% vs. 22.2%, 47.2%, 47.4%, and 55.3%, respectively), and the greatest number of T central memory cells (TCM) compared to IL-2, IL-21 and IL-2/21 (45.8% vs. 11.1%, 7.7%, and 12.1%, respectively). IL-21 and IL-2/21-expanded T cells preferentially differentiated into T naïve cells (TN) vs. those expanded in IL-2, IL-7/15 and IL-7/15/21 (27.6% and 23.2% vs. 1.7%, 4.5%, and 10.4%, respectively), and demonstrated the highest IFN-γ levels in vitro. In vivo adoptive immunotherapy (AIT) experiments demonstrated anti-tumor efficacy was equally effective using IL-2, IL-21, IL-2/21, IL-7/15 and IL-7/15/21-cultured lymphocytes vs. control or cyclophosphamide alone, even at lower doses or with greater initial size of tumor prior to treatment. Full article
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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Review

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Open AccessReview Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy
Int. J. Mol. Sci. 2017, 18(12), 2642; https://doi.org/10.3390/ijms18122642
Received: 20 November 2017 / Revised: 3 December 2017 / Accepted: 5 December 2017 / Published: 6 December 2017
Cited by 7 | PDF Full-text (490 KB) | HTML Full-text | XML Full-text
Abstract
Cancer immunotherapy has been a great breakthrough, with immune checkpoint inhibitors leading the way. Despite the clinical effectiveness of certain immune checkpoint inhibitors, the overall response rate remains low, and the effectiveness of immunotherapies for many tumors has been disappointing. There is substantial
[...] Read more.
Cancer immunotherapy has been a great breakthrough, with immune checkpoint inhibitors leading the way. Despite the clinical effectiveness of certain immune checkpoint inhibitors, the overall response rate remains low, and the effectiveness of immunotherapies for many tumors has been disappointing. There is substantial interest in looking for additional immune checkpoint molecules that may act as therapeutic targets for cancer. Recent advances during the last decade have identified several novel immune checkpoint targets, including lymphocyte activation gene-3 (LAG-3), B and T lymphocyte attenuator (BTLA), programmed death-1 homolog (PD-1H), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIM-3)/carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), and the poliovirus receptor (PVR)-like receptors. The investigations into these molecules have generated promising results in preclinical studies. Herein, we will summarize our current progress and understanding of these newly-characterized immune checkpoints and their potential application in cancer immunotherapy. Full article
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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Open AccessReview Immunotherapy for Prostate Cancer: Where We Are Headed
Int. J. Mol. Sci. 2017, 18(12), 2627; https://doi.org/10.3390/ijms18122627
Received: 22 October 2017 / Revised: 27 November 2017 / Accepted: 2 December 2017 / Published: 5 December 2017
Cited by 3 | PDF Full-text (471 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is one of the most common malignant neoplasms in men worldwide, and is the fifth cause of cancer-related death. In recent years, a new generation of therapies have been approved for the management of metastatic disease. Moreover, the development of new
[...] Read more.
Prostate cancer is one of the most common malignant neoplasms in men worldwide, and is the fifth cause of cancer-related death. In recent years, a new generation of therapies have been approved for the management of metastatic disease. Moreover, the development of new immunotherapeutic drugs has become a novel frontier for the treatment of several tumor types; to date, numerous studies have investigated their potential activity, including in prostate cancer. In this article, we discuss the role of emerging immunotherapeutic drugs in prostate cancer patients. Full article
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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Graphical abstract

Open AccessReview Targeting Immune Cell Checkpoints during Sepsis
Int. J. Mol. Sci. 2017, 18(11), 2413; https://doi.org/10.3390/ijms18112413
Received: 18 October 2017 / Revised: 10 November 2017 / Accepted: 12 November 2017 / Published: 14 November 2017
Cited by 12 | PDF Full-text (1174 KB) | HTML Full-text | XML Full-text
Abstract
Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence
[...] Read more.
Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence of secondary opportunistic infections. Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis. Engagement of these inhibitory molecules on various immune cells has been consistently shown to inhibit innate immune cell functions (e.g., phagocytosis, cytokine production and pathogen clearance) and also lead to impaired T cell competence. In numerous pre-clinical models of sepsis, therapeutic agents aimed at blocking engagement of inhibitory immune checkpoints on immune cells have been shown to improve innate and adaptive immune cell functions, increase host resistance to infection and significantly improve survival. Therefore, immunotherapy with immune cell checkpoint inhibitors holds significant potential for the future of sepsis therapy and merits further investigation. Full article
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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Open AccessReview Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints in Non-Small Cell Lung Cancer and Renal Cell Cancer: From Basic Concepts to Clinical Reality
Int. J. Mol. Sci. 2017, 18(11), 2291; https://doi.org/10.3390/ijms18112291
Received: 8 October 2017 / Revised: 26 October 2017 / Accepted: 29 October 2017 / Published: 31 October 2017
Cited by 5 | PDF Full-text (2083 KB) | HTML Full-text | XML Full-text
Abstract
In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor
[...] Read more.
In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) targeting compounds, respectively) have been successfully developed. As immune-effector cells have to enter the tumor, it is tempting to speculate that the combination of immunotherapy with AA treatment may induce synergistic effects. In this short review, we explore the theoretical background and the therapeutic potential of this novel treatment option for patients with advanced RCC or NSCLC. We discuss the growing body of evidence that pro-angiogenic factors negatively modulate the T-cell-mediated immune response and examine the preclinical evidence for testing combined immune-activating and AA therapy concepts in clinical practice. Particular attention will also be paid to potential novel treatment-related adverse events induced by combination treatment. Full article
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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Open AccessReview PD-1/PD-L1 Blockade Therapy for Tumors with Downregulated MHC Class I Expression
Int. J. Mol. Sci. 2017, 18(6), 1331; https://doi.org/10.3390/ijms18061331
Received: 26 May 2017 / Revised: 12 June 2017 / Accepted: 17 June 2017 / Published: 21 June 2017
Cited by 6 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary
[...] Read more.
The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary resistance developed. To enhance its efficacy in treated patients, predictive biomarkers are searched for and various combination treatments are intensively investigated. As the downregulation of major histocompatibility complex (MHC) class I molecules is one of the most frequent mechanisms of tumor escape from the host’s immunity, it should be considered in PD-1/PD-L1 checkpoint inhibition. The potential for the use of a PD-1/PD-L1 blockade in the treatment of tumors with aberrant MHC class I expression is discussed, and some strategies of combination therapy are suggested. Full article
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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Open AccessReview Promising Targets for Cancer Immunotherapy: TLRs, RLRs, and STING-Mediated Innate Immune Pathways
Int. J. Mol. Sci. 2017, 18(2), 404; https://doi.org/10.3390/ijms18020404
Received: 23 December 2016 / Revised: 7 February 2017 / Accepted: 7 February 2017 / Published: 14 February 2017
Cited by 13 | PDF Full-text (1668 KB) | HTML Full-text | XML Full-text
Abstract
Malignant cancers employ diverse and intricate immune evasion strategies, which lead to inadequately effective responses of many clinical cancer therapies. However, emerging data suggest that activation of the tolerant innate immune system in cancer patients is able, at least partially, to counteract tumor-induced
[...] Read more.
Malignant cancers employ diverse and intricate immune evasion strategies, which lead to inadequately effective responses of many clinical cancer therapies. However, emerging data suggest that activation of the tolerant innate immune system in cancer patients is able, at least partially, to counteract tumor-induced immunosuppression, which indicates triggering of the innate immune response as a novel immunotherapeutic strategy may result in improved therapeutic outcomes for cancer patients. The promising innate immune targets include Toll-like Receptors (TLRs), RIG-I-like Receptors (RLRs), and Stimulator of Interferon Genes (STING). This review discusses the antitumor properties of TLRs, RLRs, and STING-mediated innate immune pathways, as well as the promising innate immune targets for potential application in cancer immunotherapy. Full article
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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