A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy

Summary

Adoptive cell transfer with chimeric antigen receptor (CAR)-expressing T cells can induce remarkable complete responses in cancer patients. Therapeutic success has been correlated with central and stem cell-like memory T cell subsets in the infusion product, which are better able to drive efficient CAR T cell in vivo expansion and long-term persistence. The authors of this work, led by Prof. Denis Migliorini, previously reported that inhibition of the mitochondrial pyruvate carrier (MPC) during mouse CAR T cell culture induces a memory phenotype and enhances antitumor efficacy against melanoma. Here, they use a novel MPC inhibitor, MITO-66, which robustly induces a stem cell-like memory phenotype in CD19-CAR T cells generated from healthy donors and patients with relapsed/refractory B cell malignancies. MITO-66-conditioned CAR T cells were superior in controlling human pre-B cell acute lymphoblastic leukaemia in mice. Following adoptive cell transfer, MITO-66-conditioned CAR T cells maintained a memory phenotype and protected cured mice against tumour rechallenge. Furthermore, in an in vivo B cell leukaemia stress model, CD19-CAR T cells generated in the presence of MITO-66 largely outperformed clinical-stage AKT and PI-3Kδ inhibitors. Thus, they provide compelling preclinical evidence that MPC inhibition with MITO-66 during CAR T cell manufacturing dramatically enhances their antitumor efficacy, thereby paving the way to clinical translation.

Full article: https://doi.org/10.1016/j.omton.2024.200897

Why is it important?

CAR T cell therapy is a powerful tool against cancer, but its success is often limited by the cells' inability to persist and function optimally. This research introduces MITO-66, a novel molecule that enhances CAR T cells by maintaining a youthful, stem cell-like state. The findings of this work could dramatically improve the longevity and effectiveness of these therapies, paving the way for better outcomes in patients with aggressive cancers.

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