Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function

Nat Commun. 2020 Aug 20;11(1):4166. doi: 10.1038/s41467-020-17970-3.

Abstract

T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / immunology
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Lymphocyte Activation / immunology
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology*
  • Receptors, Chimeric Antigen / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Antigens, Neoplasm
  • Cytokines
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen