Surface downmodulation of TIM3 safeguards healthy cells but not acute myeloid leukemia from CAR T‐cell therapy

Résumé fourni par la source

Abstract T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM3), generally known as an immune checkpoint receptor, is expressed on leukemic stem and progenitor cells (LSPCs) in acute myeloid leukemia (AML), and has an active role in LSC self‐renewal. Therefore, TIM3 has been suggested as a potential target for AML treatment. Hence, we explored the feasibility of targeting TIM3 with chimeric antigen receptor (CAR) T‐cells. Despite the expression of TIM3 on activated T‐cells, TIM3 CAR T‐cells were successfully generated from different healthy individuals with excellent in vitro expansion without signs of fratricide and sustained central‐memory phenotype with minimal expression of exhaustion‐related markers, including complete loss of TIM3 expression. TIM3 loss also did not affect effector functions since TIM3 CAR T‐cells efficiently lysed TIM3 + leukemic cell lines, produced Th1‐predominant cytokines, successfully inhibited the colony‐forming of TIM3 + AML‐derived LSPCs, and showed excellent AML tumor control in xenogeneic mouse models. Notably, TIM3 CAR T‐cells did not affect healthy hematopoietic progenitor cells and healthy mature hematopoietic cells that express TIM3 at moderate levels, suggesting an optimal therapeutic window for the treatment of AML.

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