CAR-T cells with the CD38(-)CD73(-)Tim-3(-)HLA-DR(+) phenotype predict the efficacy of tisagenlecleucel as a treatment for B cell precursor ALL.

Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy is highly effective for B cell precursor acute lymphoblastic leukemia (BCP-ALL); however, approximately half of the patients relapse. Thus, there is an urgent need to identify factors that improve efficacy. This study enrolls 19 patients with BCP-ALL (16 children and 3 young adults) who receive tisagenlecleucel. Infusion products, peripheral blood, and bone marrow samples are obtained before and after CAR-T cell infusion. Single-cell analysis reveals that central memory CAR(pos) T cells increase in long-term responders, whereas CXCR3(+)CD38(high)PD-1(high) effector CAR(pos) T cells are enriched in relapsed patients, post-infusion. By contrast, CAR(pos) T cells obtained from infusion products in long-term responders are enriched in the CD38(-)CD73(-)Tim-3(-)HLA-DR(+) phenotype, characterized by a decreased ability to produce adenosine, memory-like transcriptomic characteristics, and leveraging of mitochondrial metabolism and oxidative phosphorylation. Our study reveals that the CD38(-)CD73(-)Tim-3(-)HLA-DR(+) phenotype contributes to long-term remission in patients with BCP-ALL who receive tisagenlecleucel.