Cutting the Brakes: Immunotherapy With PD-1 Inhibitors

Abstract

Immunotherapy targeting the PD-1 negative regulatory pathway has revolutionized the treatment of melanoma. The median survival for metastatic melanoma has dramatically improved over the last 5 years, from 9 months to longer than 2 years. This improvement is largely the result of to the development of anti–PD-1 targeted immunotherapy. In melanoma, durable responses have now been observed lasting many years. The field of immune checkpoint therapy, or “cutting the brakes” on antitumor immune response, is rapidly evolving, and new challenges continue to emerge in the optimal clinical use of these drugs. We review the discovery and development of anti–PD-1 therapies and the clinical successes and difficulties that have manifested with widespread use. The emergence of autoimmune toxicities and their management is a critical area of study going forward, as these toxicities can often limit the utility of these therapies in patients who otherwise would benefit. Anti–PD-1 therapy has undoubtedly been the most dramatic shift in cancer therapy in this decade, with US Food and Drug Administration approvals in melanoma and over half a dozen other cancers. Large preclinical and clinical research efforts are now aimed at understanding the immune biology driving resistance to anti–PD-1 therapy in patients with tumors that do not respond. The future is bright, but rational approaches will be necessary to have the greatest impact on the lives of melanoma patients.