Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy

Annu Rev Pharmacol Toxicol. 2016;56:59-83. doi: 10.1146/annurev-pharmtox-010814-124844.

Abstract

A chimeric antigen receptor (CAR) is a recombinant fusion protein combining an antibody-derived targeting fragment with signaling domains capable of activating T cells. Recent early-phase clinical trials have demonstrated the remarkable ability of CAR-modified T cells to eliminate B cell malignancies. This review describes the choice of target antigens and CAR manipulations to maximize antitumor specificity. Benefits and current limitations of CAR-modified T cells are discussed, with a special focus on the distribution of tumor antigens on normal tissues and the risk of on-target, off-tumor toxicities in the clinical setting. We present current methodologies for pre-evaluating these risks and review the strategies for counteracting potential off-tumor effects. Successful implementation of these approaches will improve the safety and efficacy of CAR T cell therapy and extend the range of cancer patients who may be treated.

Keywords: CARs; adoptive T cell therapy; cancer immunotherapy; chimeric antigen receptors; on/off-target effects; tumor antigens.

Publication types

  • Review

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / therapeutic use*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / therapeutic use*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins