Wei et al. comprehensively review the current understanding of the T cell-intrinsic and -extrinsic mechanisms underlying costimulatory and coinhibitory pathways that may contribute to the activity of the corresponding checkpoint blockades, with a focus on CTLA-4 and PD-1/PD-L1. Highlighting the critical gaps in the current knowledge of these mechanisms, and the even larger gaps for additional costimulatory and coinhibitory molecules, the authors call for a thorough investigation of the fundamental biology to more rationally improve the response to and safety of immune checkpoint blockade.
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); 1-18. (c)2018 AACR.
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. scwei@mdanderson.org jallison@mdanderson.org. (2) Department of Immunology, The Uni
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. scwei@mdanderson.org jallison@mdanderson.org. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. (3) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. scwei@mdanderson.org jallison@mdanderson.org. Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
