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

Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals 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 individuals with AML and tissue from 9 healthy individuals 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 and cluster of differentiation 86 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 human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development.

• • Gottschlich, A.

Thomas, M.

Grünmeier, R.

Lesch, S.

Rohrbacher, L.

Igl, V.

Briukhovetska, D.

Benmebarek, M. R.

Vick, B.

Dede, S.

Müller, K.

Xu, T.

Dhoqina, D.

Märkl, F.

Robinson, S.

Sendelhofert, A.

Schulz, H.

Umut, Ö

Kavaka, V.

Tsiverioti, C. A.

Carlini, E.

Nandi, S.

Strzalkowski, T.

Lorenzini, T.

Stock, S.

Müller, P. J.

Dörr, J.

Seifert, M.

Cadilha, B. L.

Brabenec, R.

Röder, N.

Rataj, F.

Nüesch, M.

Modemann, F.

Wellbrock, J.

Fiedler, W.

Kellner, C.

Beltrán, E.

Herold, T.

Paquet, D.

Jeremias, I.

von Baumgarten, L.

Endres, S.

Subklewe, M.

Marr, C.

Kobold, S.