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

Abstract

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.

Figure 1. Role of CTLA-4 and PD-1 in antitumor immune responses

Naïve T cells are primed by antigens presented by APCs in the context of MHC (signal 1), as well as co-stimulatory binding of CD28 to B7 (CD80/86) (signal 2). T cells upregulate CTLA-4 shortly after activation. Ligation of CTLA-4 with CD80 or CD86 limits T-cell activation and proliferation. Activated T cells traffic to the periphery and encounter tumor antigens at the tumor site. PD-1 is upregulated on T cells after prolonged activation; binding to PD-1 ligands (PD-L1 or PD-L2) expressed by tumor or other immune cells, including macrophages and dendritic cells, causes T-cell activation and dampens an ongoing antitumor immune response.

Figure 2. (A) CTLA-4 checkpoint inhibition

CTLA-4 inhibition prevents early deactivation of T cells responding to tumor antigens presented by APCs. Activated T cells can migrate to the tumor site and mount effective antitumor immune responses. Activation of T cells with cross-reactivity to host antigens may cause immunologic AEs. (B) PD-1 and PD-L1 checkpoint inhibition. PD-1 checkpoint inhibitors will prevent PD-1:PD-L1– and PD-1:PD-L2–mediated deactivation of T cells. PD-L1 checkpoint inhibitors will prevent PD-1:PD-L1– mediated deactivation of T cells. PD-1 pathway inhibition can restore antitumor immune responses directly at the tumor site and also facilitate T-cell activation in lymph nodes or other sites. Activation of T cells with cross-reactivity to host antigens may cause immunologic AEs.

Figure 3. Kinetics of irAEs in ipilimumab-treated patients

The overall approximate timing and relative grade of the most common irAEs in ipilimumab-treated melanoma patients is depicted. Individual patient experiences vary. Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved. Weber JS et al: J Clin Oncol. 30 (21), 2012: 2691–2697 [38].