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.

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.