Engineering Cytoplasmic Signaling of CD28ζ CARs for Improved Therapeutic Functions

Front Immunol. 2020 Jun 19:11:1046. doi: 10.3389/fimmu.2020.01046. eCollection 2020.

Abstract

Chimeric antigen receptor modified T cells (CAR-T) have yielded impressive clinical outcomes in treating hematopoietic malignancies. However, relapses have occurred in a substantial number of patients and limited the development of CAR-T therapy. Most underlying reasons for these relapses can be attributed to poor persistence and rapid exhaustion of CAR-T cells in vivo. Despite multiple strategies having been developed, how to improve CAR-T persistence or resist exhaustion while maintaining sufficient cytotoxic functions is still a great challenge. Here we discuss engineering cytoplasmic signaling as an important strategy for CAR optimization. This review summarizes recent advances showing that the anti-tumor function of CAR-T cells can be improved by optimizing the CD3ζ domain or downstream signaling of CD28ζ CAR.

Keywords: CD3ζ; ITAM; chimeric antigen receptor; cytotoxicity; persistence; signal strength.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • CD28 Antigens / chemistry
  • CD28 Antigens / immunology*
  • CD3 Complex / chemistry
  • CD3 Complex / immunology
  • Cell Engineering / methods
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Lymphocyte Activation
  • Models, Immunological
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Protein Domains
  • Receptors, Chimeric Antigen / chemistry
  • Receptors, Chimeric Antigen / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology

Substances

  • CD28 Antigens
  • CD3 Complex
  • CD3 antigen, zeta chain
  • Receptors, Chimeric Antigen