Immune checkpoints and immunotherapy for colorectal cancer

Abstract

Colorectal cancer (CRC) remains one of the major causes of death worldwide, despite steady improvement in early detection and overall survival over the past decade. Current treatment paradigms, with chemotherapy and biologics, appear to have reached their maximum benefit. Immunotherapy, especially with checkpoint inhibitors, has shown considerable clinical benefit in various cancers, including mismatch-repair-deficient CRC. This has led to the planning and initiation of several clinical trials evaluating novel immunotherapy agents-as single agents, combinations and in conjunction with chemotherapy-in patients with CRC. This article reviews biological and preclinical data for checkpoint inhibitors and discusses various immunotherapy trials in CRC, as well as current efforts in CRC immunotherapy.

Keywords: checkpoint inhibition/blockade; colorectal cancer; cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); immunotherapy; pembrolizumab; programmed death 1 (PD-1); vaccine.

Figure 1.

Checkpoint blockade in tumor immunotherapy. T-cells initiate the immune response though recognition of antigenic peptides presented by the MHC on the surface of antigen-presenting cells and cancer cells through their TCR. TCR engagement alone is insufficient to turn on a T-cell response, and additional co-stimulatory signal via B7 are required for cytokine production, targeT-cell lysis and effector cell responses. B7 protein can pair with CD28 on T-cells, leading to amplification of TCR signaling, or CTLA-4 on a T-cell inhibiting T-cell activation. PD-1 primarily inhibits effector T-cell activity in the effector phase within tissue and tumors—unlike CTLA-4, which mainly modulates early steps in T-cell activation. PD-1 inhibitory receptor is expressed by T-cells during long-term antigen exposure and results in inhibition of T-cells on interaction with PD-L1, which is expressed in the tumor microenvironment. Immune checkpoint blockade via monoclonal antibodies leads to preferential activation of cancer-specific T-cells and revival of tumor immunity (MHC: major histocompatibility complex; TCR: T-cell receptor; CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; PD-1: programmed death 1; PD-L1: programmed death-ligand 1).