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- Title
Replacing CAR-T cell resistance with persistence by changing a single residue.
- Authors
Hsieh, Emily M.; Scherer, Lauren D.; Rouce, Rayne H.
- 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.
- Subjects
RESISTANCE to change; CHIMERIC antigen receptors; HEMATOLOGIC malignancies; PANCREATIC cancer; CELLULAR therapy
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 6, p2806
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI136872