Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia

Chimeric-antigen receptor (CAR) T cells have emerged as a powerful treatment option for patients with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here, we leveraged an atlas of publicly available RNA sequencing data of over 500,000 single cells from 15 AML patients and nine healthy human tissues for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this, high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor (CSF1R) and cluster of differentiation 86 (CD86) as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line and patient-derived AML models with minimal off-target toxicity towards relevant healthy human tissues. This provides strong rationale for further clinical development.