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Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

By Sonia Guedan, Aviv Madar, Victoria Casado-Medrano, Carolyn Shaw, Anna Wing, Feng Liu, Regina Young, Carl H. June and Avery D. Jr. Posey

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

Publisher: 'American Society for Clinical Investigation'
Year: 2020
DOI identifier: 10.1172/JCI133215
OAI identifier: oai:oak.novartis.com:40717
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