Guedan, Sonia, Madar, Aviv, Casado-Medrano, Victoria, Shaw, Carolyn, Wing, Anna, Liu, Feng, Young, Regina, June, Carl H. and Posey, Avery D. Jr. (2020) Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability. Journal of Clinical Investigation. ISSN 0021-97381558-8238

Abstract

Chimeric antigen receptor–T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and 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 changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.

Item Type:	Article
Keywords:	Cancer immunotherapy Immunology T cells Therapeutics
Date Deposited:	19 May 2020 00:45
Last Modified:	19 May 2020 00:45
URI:	https://oak.novartis.com/id/eprint/40717