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Mechanisms of Resistance to PD-1 and PD-L1 Blockade

Nowicki, Theodore, S., MD, PhD*; Hu-Lieskovan, Siwen, MD, PhD; Ribas, Antoni, MD, PhD†‡§∥

doi: 10.1097/PPO.0000000000000303
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Cancer immunotherapy utilizing blockade of the PD-1/PD-L1 checkpoint has revolutionized the treatment of a wide variety of malignancies, leading to durable therapeutic responses not typically seen with traditional cytotoxic anticancer agents. However, these therapies are ineffective in a significant percentage of patients, and some initial responders eventually develop resistance to these therapies with relapsed disease. The mechanisms leading to both primary and acquired resistance to PD-1/PD-L1 inhibition are varied and can be both multifactorial and overlapping in an individual patient. As the mechanisms of resistance to PD-1/PD-L1 blockade continue to be further characterized, new strategies are being developed to prevent or reverse resistance to therapy, leading to improved patient outcomes.

From the *Division of Pediatric Hematology-Oncology, Department of Pediatrics, and †Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles; ‡Jonsson Comprehensive Cancer Center; and §Department of Molecular and Medical Pharmacology and ∥Division of Surgical-Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA.

This research was supported by the Parker Institute for Cancer Immunotherapy, National Institutes of Health/National Cancer Institute grants R35 CA197633 and P01 CA168585 (to A.R.), the Ressler Family Fund, the Garcia-Corsini Family Fund, the Samuels Family Fund, and the Grimaldi Family Fund (to A.R.). S.H.-L. is supported by a Career Development Award from the American Society of Clinical Oncology, a SU2C/AACR Phil Sharp Award, a Melanoma Foundation Alliance Young Investigator Award, and a UCLA KL2 Award. T.S.N. is supported by the National Institutes of Health/National Institute of Child Health and Human Development grant K12-HD000850 (Pediatric Scientist Development Program).

The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, the National Cancer Institute, the National Institute of Child Health and Human Development, the Parker Institute for Cancer Immunotherapy, the Grimaldi Family Fund, the Samuels Family Fund, the Garcia-Corsini Family Fund, or the Ressler Family Foundation.

Reprints: Antoni Ribas, University of California Los Angeles, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA, 90095. E-mail: aribas@mednet.ucla.edu.

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