PD-1 as a potential target in cancer therapy

Abstract

Recently, an improved understanding of the molecular mechanisms governing the host response to tumors has led to the identification of checkpoint signaling pathways involved in limiting the anticancer immune response. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway, normally involved in promoting tolerance and preventing tissue damage in settings of chronic inflammation. Many human solid tumors express PD ligand 1 (PD-L1), and this is often associated with a worse prognosis. Tumor-infiltrating lymphocytes from patients with cancer typically express PD-1 and have impaired antitumor functionality. Proof-of-concept has come from several preclinical studies in which blockade of PD-1 or PD-L1 enhanced T-cell function and tumor cell lysis. Three monoclonal antibodies against PD-1, and one against PD-L1, have reported phase 1 data. All four agents have shown encouraging preliminary activity, and those that have been evaluated in larger patient populations appear to have encouraging safety profiles. Additional data are eagerly awaited. This review summarizes emerging clinical data and potential of PD-1 pathway-targeted antibodies in development. If subsequent investigations confirm the initial results, it is conceivable that agents blocking the PD-1/PD-L1 pathway will prove valuable additions to the growing armamentarium of targeted immunotherapeutic agents.

Keywords: Cancer; immune tolerance; immunotherapy; nivolumab; programmed cell death-1 receptor; programmed cell death-1-ligand 1.

Figure 1

PD-1 in T-cell activation, exhaustion, and effector function. (A) T cells are activated via (1) binding of MHC plus peptide on an APC to the TCR and then (2) binding of APC CD80/86 to T-cell CD28. In patients with cancer, tumor cells can also serve as APCs. Upon T-cell activation, PD-1 expression is induced. (B) In situations of chronic infection or persistent stimulation, PD-L1 signals through T-cell PD-1 to “turn off” T cells in order to minimize damage to healthy tissue. Tumor cells can upregulate PD-L1 in order to “turn off” T cells that might destroy them. (C) Blocking the PD-1/PD-L1 signaling pathway allows T cells to maintain their effector functions. In patients with cancer, activated tumor-specific T cells can kill tumor cells and secrete cytokines that activate/recruit other immune cells to participate in the antitumor response. APC, antigen-presenting cell; IFN-γ, interferon gamma; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, PD ligand 1; TCR, T-cell receptor.

Figure 2

Increased PD-L1 expression (≥10% vs. <10%) diminishes survival in RCC. From Thompson et al. . Copyright 2012 National Academy of Sciences, U.S.A. Reprinted with permission.

Figure 3

Durable responses in a cohort of patients with MEL treated with 1 mg/kg nivolumab. From Topalian et al. . Copyright 2012 Massachusetts Medical Society. Reprinted with permission.