Immune Checkpoint Blockade in Cancer Therapy

Abstract

Immunologic checkpoint blockade with antibodies that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have demonstrated promise in a variety of malignancies. Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade are being investigated to determine whether they enhance the efficacy of either approach alone. Principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

The cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) immunologic checkpoint. T-cell activation requires antigen presentation in the context of a major histocompatibility complex (MHC) molecule in addition to the costimulatory signal achieved when B7 on an antigen-presenting cell (dendritic cell shown) interacts with CD28 on a T cell. Early after activation, to maintain immunologic homeostasis, CTLA-4 is translocated to the plasma membrane where it downregulates the function of T cells.

Fig 2.

The programmed cell death protein 1 (PD-1) immunologic checkpoint. PD-1 is expressed on activated T cells. Interactions between PD-1 and its ligands, PD-L1 and PD-L2, are complex and occur at multiple steps of an immune response. For illustration, we have shown an interaction early after activation in the lymph node where PD-L1/PD-L2 on an antigen-presenting cell (dendritic cell shown) negatively regulates T-cell activity through PD-1 and through an interaction between B7 and PD-L1. The PD-1 pathway is also likely important in the tumor microenvironment where PD-L1 expressed by tumors interacts with PD-1 on T cells to suppress T-cell effector function. MHC, major histocompatibility complex.