Replacing CAR-T cell resistance with persistence by changing a single residue

Abstract

Sustained persistence of chimeric antigen receptor T (CAR-T) cells is a key characteristic associated with long-term remission in patients with hematologic malignancies. Attempts to uncover mechanisms that enhance persistence and thus functionality will have a substantial impact in broadening application of CAR-T cell therapy, especially for solid tumors. In this issue of the JCI, Guedan et al. describe a promising strategy to limit T cell exhaustion and improve persistence by changing a single amino acid in the costimulatory domain of CD28. The authors demonstrated that this single amino acid substitution in CD28-based mesothelin CAR-T cells results in improved persistence and functionality in a xenograft model of pancreatic cancer. Furthermore, reciprocal alteration of the same residue in inducible costimulator-containing (ICOS-containing) CAR-T cells resulted in limited antitumor activity and persistence. These findings suggest that simple alterations in the costimulatory domain may enhance CAR-T cell persistence, warranting future evaluation in other CD28-costimulatory CARs in an effort to improve durable antitumor effects.

Figure 1. Possible mechanisms of improved persistence in CD28-YMFM–costimulatory CAR-T cells.

Signaling pathways proposed by Guedan and colleagues (21) suggest that second-generation CARs with costimulatory domains containing a single amino acid substitution YMNM (yellow) or YMFM (blue) differentially interact with VAV1/Grb2. CD28-YMNM CAR T cells show increased activation (++) and additive activation (+++) from multiple pathways. CD28-YMFM CAR-T cells show decreased NFAT activation, IL-2 production, calcium release, with T cell persistence.