RT Journal Article
SR Electronic
T1 CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 62
OP 74
DO 10.1158/2326-6066.CIR-20-0253
VO 9
IS 1
A1 Boucher, Justin C.
A1 Li, Gongbo
A1 Kotani, Hiroshi
A1 Cabral, Maria L.
A1 Morrissey, Dylan
A1 Lee, Sae Bom
A1 Spitler, Kristen
A1 Beatty, Nolan J.
A1 Cervantes, Estelle V.
A1 Shrestha, Bishwas
A1 Yu, Bin
A1 Kazi, Aslamuzzaman
A1 Wang, Xuefeng
A1 Sebti, Said M.
A1 Davila, Marco L.
YR 2021
UL http://cancerimmunolres.aacrjournals.org/content/9/1/62.abstract
AB 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.