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Special Issue "Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editor

Prof. Dr. Donald J. Buchsbaum
E-Mail Website
Guest Editor
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: cancer immunotherapy; radioimmunotherapy; monoclonal antibody therapy; targeting cancer stem cells; TRAIL-DR5 therapy; Wnt/β-catenin inhibitors
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Immune checkpoints are regulators of the immune system. Checkpoint-inhibitor monoclonal antibodies that block CTLA-4 or PD1/PD-L1 have been approved for the treatment of several cancers including melanoma, bladder, and lung cancer. Despite increases in overall survival, not all patients respond to this treatment. Approaches to increase survival include the use of new checkpoint inhibitors to regulate T cell responses and other immune effectors, identification of predictive biomarkers and modulators of the immune response, and the use of combination immunotherapies and therapies. This special will incorporate, but is not limited to, the following sub-topics:

  • Novel checkpoints and inhibitors
  • Immune checkpoint activators
  • Immune regulation
  • Biomarkers predictive of response
  • Immunomodulatory agents including cytokines
  • Targeting of innate immunity
  • Adaptive immunity
  • Neoantigen-targeted therapies
  • T cell exhaustion
  • Targeting of immunosuppressive cells
  • Mechanisms of tumor immune cell evasion
  • Modulation of immunosuppressive tumor microenvironment
  • Targeting Wnt ligand signaling

Prof. Dr. Donald J. Buchsbaum
Guest Editor

Manuscript Submission Information

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Keywords

  • Cancer immunotherapy
  • Checkpoint inhibitors
  • Innate immunity
  • Adaptive immunity
  • Immunosuppression
  • Immunomodulation

Published Papers (10 papers)

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Research

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Article
Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade
Int. J. Mol. Sci. 2020, 21(5), 1806; https://doi.org/10.3390/ijms21051806 - 06 Mar 2020
Cited by 1 | Viewed by 1143
Abstract
Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of [...] Read more.
Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Article
Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding
Int. J. Mol. Sci. 2020, 21(2), 636; https://doi.org/10.3390/ijms21020636 - 18 Jan 2020
Cited by 6 | Viewed by 1371
Abstract
Immune checkpoints are crucial in the maintenance of antitumor immune responses. The activation or blockade of immune checkpoints is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals, including the enhancement or suppression of T-cell proliferation, [...] Read more.
Immune checkpoints are crucial in the maintenance of antitumor immune responses. The activation or blockade of immune checkpoints is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals, including the enhancement or suppression of T-cell proliferation, differentiation, and/or cytokine secretion. B-and T-lymphocyte attenuator (BTLA) is a lymphoid-specific cell surface receptor which is present on T-cells and interacts with herpes virus entry mediator (HVEM), which is present on tumor cells. The binding of HVEM to BTLA triggers an inhibitory signal which attenuates the immune response. This feature is interesting for studying the molecular interactions between HVEM and BTLA, as they may be targeted for novel immunotherapies. This work was based on the crystal structure of the BTLA/HVEM complex showing that BTLA binds the N-terminal cysteine-rich domain of HVEM. We investigated the amino acid sequence of HVEM and used molecular modeling methods to develop inhibitors of the BTLA/HVEM interaction. We synthesized novel compounds and determined their ability to interact with the BTLA protein and inhibit the formation of the BTLA/HVEM complex. Our results suggest that the HVEM (14–39) peptide is a potent inhibitor of the formation of the BTLA/HVEM protein complex. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Article
Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis
Int. J. Mol. Sci. 2020, 21(2), 448; https://doi.org/10.3390/ijms21020448 - 10 Jan 2020
Cited by 3 | Viewed by 1433
Abstract
Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off [...] Read more.
Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64–1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Review

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Review
Immunotherapy for Uterine Cervical Cancer Using Checkpoint Inhibitors: Future Directions
Int. J. Mol. Sci. 2020, 21(7), 2335; https://doi.org/10.3390/ijms21072335 - 27 Mar 2020
Cited by 7 | Viewed by 1673
Abstract
Immune checkpoint inhibitors (ICIs) have demonstrated marked clinical effects worldwide, and “cancer immunotherapy” has been recognized as a feasible option for cancer treatment. Significant treatment responses have already been attained for malignant melanoma and lung cancer, ahead of gynecologic cancer. In cervical cancer, [...] Read more.
Immune checkpoint inhibitors (ICIs) have demonstrated marked clinical effects worldwide, and “cancer immunotherapy” has been recognized as a feasible option for cancer treatment. Significant treatment responses have already been attained for malignant melanoma and lung cancer, ahead of gynecologic cancer. In cervical cancer, however, results are only available from phase II trials, not from phase III trials. Cervical cancer is a malignant tumor and is the fourth most common cancer among women worldwide. Since the introduction of angiogenesis inhibitors, treatment for recurrent and advanced cervical cancers has improved in the past five years, but median overall survival is 16.8 months for advanced cervical cancer, and all-stage five-year overall survival rate is 68%, indicating that treatment effects remain inadequate. For this reason, the development of new therapeutic approaches is imperative. We describe herein the KEYNOTE-158 and CheckMate 358 clinical trials, which were conducted for cervical cancer, and discuss future directions, including potential combinations with concurrent chemoradiation therapy (CCRT), as noted for other types of cancer. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Review
Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives
Int. J. Mol. Sci. 2020, 21(7), 2286; https://doi.org/10.3390/ijms21072286 - 26 Mar 2020
Cited by 16 | Viewed by 1255
Abstract
The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer [...] Read more.
The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer cells has always attracted the scientific community and is the basis for the development of new promising cancer therapies. Recent evidence has highlighted how extracellular vesicles (EVs) represent a mechanism by which cancer cells promote immune escape by inducing phenotypic changes on different immune cell populations. In this review, we will discuss the recent findings on the role of tumor-derived extracellular vesicles (TEVs) in regulating immune checkpoints, focusing on the PD-L1/PD-1 axis. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Review
Determinants of Resistance to Checkpoint Inhibitors
Int. J. Mol. Sci. 2020, 21(5), 1594; https://doi.org/10.3390/ijms21051594 - 26 Feb 2020
Cited by 13 | Viewed by 1150
Abstract
The development of immune checkpoint inhibitors (ICIs) has drastically altered the landscape of cancer treatment. Since approval of the first ICI for the treatment of advanced melanoma in 2011, several therapeutic agents have been Food and Drug Administration (FDA)-approved for multiple cancers, and [...] Read more.
The development of immune checkpoint inhibitors (ICIs) has drastically altered the landscape of cancer treatment. Since approval of the first ICI for the treatment of advanced melanoma in 2011, several therapeutic agents have been Food and Drug Administration (FDA)-approved for multiple cancers, and hundreds of clinical trials are currently ongoing. These antibodies disrupt T-cell inhibitory pathways established by tumor cells and thus re-activate the host’s antitumor immune response. While successful in many cancers, several types remain relatively refractory to treatment or patients develop early recurrence. Hence, there is a great need to further elucidate mechanisms of resistant disease and determine novel, effective, and tolerable combination therapies to enhance efficacy of ICIs. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
Review
The Role of Immune Checkpoint Blockade in Uveal Melanoma
Int. J. Mol. Sci. 2020, 21(3), 879; https://doi.org/10.3390/ijms21030879 - 29 Jan 2020
Cited by 13 | Viewed by 1818
Abstract
Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. [...] Read more.
Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Review
Mass Spectrometry-Based Multivariate Proteomic Tests for Prediction of Outcomes on Immune Checkpoint Blockade Therapy: The Modern Analytical Approach
Int. J. Mol. Sci. 2020, 21(3), 838; https://doi.org/10.3390/ijms21030838 - 28 Jan 2020
Cited by 3 | Viewed by 1321
Abstract
The remarkable success of immune checkpoint inhibitors (ICIs) has given hope of cure for some patients with advanced cancer; however, the fraction of responding patients is 15–35%, depending on tumor type, and the proportion of durable responses is even smaller. Identification of biomarkers [...] Read more.
The remarkable success of immune checkpoint inhibitors (ICIs) has given hope of cure for some patients with advanced cancer; however, the fraction of responding patients is 15–35%, depending on tumor type, and the proportion of durable responses is even smaller. Identification of biomarkers with strong predictive potential remains a priority. Until now most of the efforts were focused on biomarkers associated with the assumed mechanism of action of ICIs, such as levels of expression of programmed death-ligand 1 (PD-L1) and mutation load in tumor tissue, as a proxy of immunogenicity; however, their performance is unsatisfactory. Several assays designed to capture the complexity of the disease by measuring the immune response in tumor microenvironment show promise but still need validation in independent studies. The circulating proteome contains an additional layer of information characterizing tumor–host interactions that can be integrated into multivariate tests using modern machine learning techniques. Here we describe several validated serum-based proteomic tests and their utility in the context of ICIs. We discuss test performances, demonstrate their independence from currently used biomarkers, and discuss various aspects of associated biological mechanisms. We propose that serum-based multivariate proteomic tests add a missing piece to the puzzle of predicting benefit from ICIs. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Review
Possibilities of Improving the Clinical Value of Immune Checkpoint Inhibitor Therapies in Cancer Care by Optimizing Patient Selection
Int. J. Mol. Sci. 2020, 21(2), 556; https://doi.org/10.3390/ijms21020556 - 15 Jan 2020
Cited by 8 | Viewed by 1325
Abstract
Immune checkpoint inhibitor (ICI) therapies have become the most important medical therapies in many malignancies, such as melanoma, non-small-cell lung cancer, and urogenital cancers. However, due to generally low response rates of PD-(L)1 monotherapy, both PD-(L)1 combination therapies and novel therapeutics are under [...] Read more.
Immune checkpoint inhibitor (ICI) therapies have become the most important medical therapies in many malignancies, such as melanoma, non-small-cell lung cancer, and urogenital cancers. However, due to generally low response rates of PD-(L)1 monotherapy, both PD-(L)1 combination therapies and novel therapeutics are under large-scale clinical evaluation. Thus far, clinical trials have rather suboptimally defined the patient population most likely to benefit from ICI therapy, and there is an unmet need for negative predictive markers aiming to reduce the number of non-responding patients in clinical practice. Furthermore, there is a strong need for basic tumor immunology research and innovative clinical trials to fully unleash the potential of ICI combinations for the benefit of patients. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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Review
Prognostic Factors and Biomarkers of Responses to Immune Checkpoint Inhibitors in Lung Cancer
Int. J. Mol. Sci. 2019, 20(19), 4931; https://doi.org/10.3390/ijms20194931 - 05 Oct 2019
Cited by 17 | Viewed by 2358
Abstract
Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown [...] Read more.
Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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