SIDEBAR: Understanding the PD-1/PD-L1 Pathway and Its Promise 

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This trial has revealed synergies with anti-PD-1 and anti-CTLA-4. Targeting of these pathways has the potential to disrupt the natural function of PD-1 and CTLA-4 in tolerance and the termination of immune responses.

—Arlene H. Sharpe, MD, PhD

Tumors can be recognized by the immune system, but they have multiple mechanisms for evading eradication by the immune system. The tumor microenvironment suppresses the immune response, partly because tumors can express molecules that inhibit immune responses. The cancer clinical trials summarized by Dr. Herbst and Dr. Wolchok use a new strategy that blocks major pathways the tumor uses to suppress the immune response.

Underlying Mechanisms

Immunoinhibitory receptors regulate T-cell activation, tolerance, and “exhaustion.” T-cell exhaustion is a dysfunctional state that develops in the setting of chronic antigen stimulation (such as occurs in a chronic infection or tumor). Immune responses against tumors are an ongoing chronic fight. Multiple inhibitory receptors contribute to T-cell exhaustion, and these are targets for immunotherapy. Tumor infiltrating lymphocytes can express many immunoinhibitory receptors, and these are druggable targets for immunotherapy. This inhibitory strategy is often called “checkpoint blockade.”

The PD-1 pathway is an important immunoinhibitory pathway that inhibits tumor-specific T cells. The PD-1 pathway is a key mediator of T-cell exhaustion; blockade of this pathway can reinvigorate exhausted T cells, enabling them to expand and perform effector functions (such as killing tumor cells). PD-1 is highly expressed on tumor-infiltrating lymphocytes, and these are functionally exhausted T cells.

PD-1 has two ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors and inhibits immune attack. PD-L1 is also expressed on a variety of hematopoietic cells (eg, dendritic cells and macrophages) as well as nonhematopoietic cells (eg, stromal cells, vascular endothelial cells). PD-L1 on these cell types also can inhibit T-cell responses. The PD-L1:PD-1 pathway has a natural role in regulating T-cell tolerance and termination of immune responses. Tumors exploit PD-L1 and use it to inhibit immune responses.

Herbst and colleagues target the PD-1 pathway using a blocking antibody to PD-L1. Anti-PD-L1 antibodies have the potential to exert their effects by blocking PD-L1 on tumor cells, hematopoietic cells, or nonhematopoietic cells. Herbst and colleagues correlate functional response to anti-PD-L1 with PD-L1 expression on the tumor.

Synergistic Inhibition

T cells often coexpress several inhibitory receptors. Studies in animal models have shown that coblockade of two inhibitory pathways enables better rescue of exhausted T cells than PD-1/PD-L1 blockade alone. Wolchok and colleagues use a strategy that targets two inhibitory receptors—CTLA-4 and PD-1—to promote antitumor immunity.

The FDA-approved anti-CTLA-4 antibody (ipilimumab [Yervoy]) is the first in this class of tumor immunotherapy agents that target inhibitory receptors. The goal of the study by Wolchok and colleagues is to further improve antitumor immunity and tumor eradication by simultaneously targeting the CTLA-4 and PD-1 inhibitory pathways. This trial has revealed synergies with anti-PD-1 and anti-CTLA-4.

In addition to their inhibitory roles in cancer and chronic infections, PD-1 and CTLA-4 also have roles in controlling T-cell tolerance and the strength and duration of immune responses. Targeting of these pathways has the potential to disrupt the natural function of PD-1 and CTLA-4 in tolerance and the termination of immune responses.

The success of these therapies is a balance between activating antitumor immunity and breaking tolerance. Some adverse events of an immunologic nature are seen and need to be anticipated and managed. Combination therapy has the potential to have a greater impact on T-cell tolerance than targeting each pathway alone. The clinical trial design employed several dose and sequence combination strategies to determine the combination that best promotes effective antitumor immunity.■

Dr. Sharpe is George Fabyan Professor of Comparative Pathology, Department of Microbiology and Immunobiology, and Co-Director, Harvard Institute of Translational Immunology, Harvard Medical School, Boston.

Disclosure: Dr. Sharpe has patents in the PD-1 pathway that have been licensed to Roche/Genentech, BMS, Merck, DMD Serono, Boehringer Ingelheim, Amplimmune, and Costim Pharmaceuticals. She is also the cofounder of Costim Pharmaceuticals.

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