PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma

Jason J. Luke _ and Patrick A. Ott

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Oncotarget. 2015; 6:3479-3492. https://doi.org/10.18632/oncotarget.2980

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Jason J. Luke1, Patrick A. Ott2

1Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

2Melanoma Disease Center, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

Correspondence to:

Jason J. Luke, e-mail: [email protected]

Keywords: immunotherapy, melanoma, programmed death 1 pathway, PD-1, adverse events

Received: October 10, 2014     Accepted: December 21, 2014     Published: February 17, 2015


Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors, including discussion of their novel mechanism of action and clinical data to-date, with a focus on melanoma.

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