Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability
- 1 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (6), 3087-3097
- https://doi.org/10.1172/jci133215
Abstract
Chimeric antigen receptor (CAR) T cell therapies can eliminate relapsed and refractory tumors, but the durability of anti-tumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, as well as influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and substituting this asparagine to phenylalanine (CD28-YMFM) promoted durable anti-tumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing towards Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and anti-tumor activity. This finding suggests modifications to the co-stimulatory domains of CAR-T cells can enable longer persistence and thereby improve anti-tumor response.Funding Information
- National Cancer Institute (P01CA214278,P01CA066726,R01CA120409)
- U.S. Department of Veterans Affairs (IK2BX004183)
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