The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) immune checkpoints are negative regulators of T-cell immune function. Inhibition of these targets, resulting in increased activation of the immune system, has led to new immunotherapies for melanoma, non–small cell lung cancer, and other cancers. Ipilimumab, an inhibitor of CTLA-4, is approved for the treatment of advanced or unresectable melanoma. Nivolumab and pembrolizumab, both PD-1 inhibitors, are approved to treat patients with advanced or metastatic melanoma and patients with metastatic, refractory non-small cell lung cancer. In addition the combination of ipilimumab and nivolumab has been approved in patients with BRAF WT metastatic or unresectable melanoma. The roles of CTLA-4 and PD-1 in inhibiting immune responses, including antitumor responses, are largely distinct. CTLA-4 is thought to regulate T-cell proliferation early in an immune response, primarily in lymph nodes, whereas PD-1 suppresses T cells later in an immune response, primarily in peripheral tissues. The clinical profiles of immuno-oncology agents inhibiting these 2 checkpoints may vary based on their mechanistic differences. This article provides an overview of the CTLA-4 and PD-1 pathways and implications of their inhibition in cancer therapy.
*Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School
†Biologic Therapy Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Professional medical writing assistance was provided by Britt Anderson, PhD, and professional editing assistance was provided by Lisa Sullivan at StemScientific, an Ashfield company, and was funded by Bristol-Myers Squibb. Bristol-Myers Squibb generated the concept for this review article; however, the authors developed the content. Bristol-Myers Squibb reviewed a draft for medical accuracy only. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript.
E.I.B. received research funding from Bristol-Myers Squibb, Genentech, and Merck; spouse previously employed by Merck. A.D. declares no conflicts of interest.
Reprints: Elizabeth I. Buchbinder, MD, Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215. E-mail: email@example.com.
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