Journal
JCI INSIGHT
Volume 5, Issue 21, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.136093
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Funding
- NIH [1R01CA173750, P01CA094237, GM008231, P01CA096832, R50CA211481]
- American Lebanese Syrian Associated Charities
- National Cancer Institute of the NIH [P30CA021765]
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Chimeric antigen receptor (CAR) T cell therapy for solid tumors has shown limited efficacy in early-phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains, and we explored whether MyD88 and CD40 (MC) costimulatory endodomains in CARs could improve their antitumor activity. We generated CD28-, 41BB-, and MC-CART cells and demonstrated that MC-EAR T cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and were activated at baseline. After stimulation, MC-CART cells remained in a less differentiated state than CD28and 41BB-CAR T cells as judged by low levels of transcription factor TBET and B lymphocyte induced maturation protein 1 expression and tower cytolytic activity in comparison with CD28- and 41BB-EAR T cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T cell therapy approaches for solid tumors.
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