CD28 costimulatory domain⇓targeted mutations enhance chimeric antigen receptor T-cell function

Justin C. Boucher, Gongbo Li, Hiroshi Kotani, Maria L. Cabral, Dylan Morrissey, Sae Bom Lee, Kristen Spitler, Nolan J. Beatty, Estelle V. Cervantes, Bishwas Shrestha, Bin Yu, Aslamuzzaman Kazi, Xuefeng Wang, Said M. Sebti, Marco L. Davila*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

An obstacle to the development of chimeric antigen receptor (CAR) T cells is the limited understanding of CAR T-cell biology and the mechanisms behind their antitumor activity. We and others have shown that CARs with a CD28 costimulatory domain drive high T-cell activation, which leads to exhaustion and shortened persistence. This work led us to hypothesize that by incorporating null mutations of CD28 subdomains (YMNM, PRRP, or PYAP), we could optimize CAR T-cell costimulation and enhance function. In vivo, we found that mice given CAR T cells with only a PYAP CD28 endodomain had a significant survival advantage, with 100% of mice alive after 62 days compared with 50% for mice with an unmutated endodomain. We observed that mutant CAR T cells remained more sensitive to antigen after ex vivo antigen and PD-L1 stimulation, as demonstrated by increased cytokine production. The mutant CAR T cells also had a reduction of exhaustion-related transcription factors and genes such as Nfatc1, Nr42a, and Pdcd1. Our results demonstrated that CAR T cells with a mutant CD28 endodomain have better survival and function. This work allows for the development of enhanced CAR T-cell therapies by optimizing CAR T-cell costimulation.

Original languageEnglish (US)
Pages (from-to)OF1-OF13
JournalCancer Immunology Research
Volume9
Issue number4
DOIs
StatePublished - Apr 2021
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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