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Immune checkpoint
About: Immune checkpoint is a research topic. Over the lifetime, 7807 publications have been published within this topic receiving 243553 citations.
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TL;DR: This work discusses biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria and suggests mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.
Abstract: With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.
1,901 citations
TL;DR: The current state of understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, is reviewed, and conceptual gaps in knowledge are highlighted.
Abstract: Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge. Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069–86. ©2018 AACR.
1,893 citations
TL;DR: It is proposed that intercrossing research in molecular immunology and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.
1,766 citations
TL;DR: It is reported that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface, suggesting a mechanism by which tumours could evade the immunesystem, and the potential application ofExosomal PD- L1 to monitor patient responses to checkpoint therapies.
Abstract: Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2–4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy. Melanoma cells release programmed death-ligand 1 (PD-L1) on the surface of circulating exosomes, suggesting a mechanism by which tumours could evade the immunesystem, and the potential application of exosomal PD-L1 to monitor patient responses to checkpoint therapies.
1,591 citations
TL;DR: This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines.
1,569 citations