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Review

Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

Spencer C. Wei, Colm R. Duffy and James P. Allison
Spencer C. Wei
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: scwei@mdanderson.org jallison@mdanderson.org
Colm R. Duffy
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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James P. Allison
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: scwei@mdanderson.org jallison@mdanderson.org
DOI: 10.1158/2159-8290.CD-18-0367 Published September 2018
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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.

  • Received April 4, 2018.
  • Revision received June 4, 2018.
  • Accepted July 11, 2018.
  • Published first August 16, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Discovery: 8 (9)
September 2018
Volume 8, Issue 9
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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Spencer C. Wei, Colm R. Duffy and James P. Allison
Cancer Discov September 1 2018 (8) (9) 1069-1086; DOI: 10.1158/2159-8290.CD-18-0367

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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Spencer C. Wei, Colm R. Duffy and James P. Allison
Cancer Discov September 1 2018 (8) (9) 1069-1086; DOI: 10.1158/2159-8290.CD-18-0367
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  • Article
    • Abstract
    • Introduction
    • Mechanisms of CTLA4-Mediated Negative Costimulation
    • Mechanisms of PD-1–Mediated Attenuation of T-Cell Activity
    • Mechanisms of Negative Costimulation Versus Mechanisms of Checkpoint Blockade
    • Mechanisms of Action of CTLA4 Blockade–Induced Tumor Rejection
    • Mechanisms of Action of PD-1 Blockade–Induced Tumor Rejection
    • Therapeutic Combinations
    • Beyond CTLA4 and PD-1
    • Concluding Remarks
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • References
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