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

Gottschlich, Adrian; Thomas, Moritz; Gruenmeier, Ruth; Lesch, Stefanie; Rohrbacher, Lisa; Igl, Veronika; Briukhovetska, Daria; Benmebarek, Mohamed-Reda; Vick, Binje; Dede, Sertac; Mueller, Katharina; Xu, Tao; Dhoqina, Dario; Maerkl, Florian; Robinson, Sophie; Sendelhofert, Andrea; Schulz, Heiko; Umut, Oeykue; Kavaka, Vladyslav; Tsiverioti, Christina Angeliki; Carlini, Emanuele; Nandi, Sayantan; Strzalkowski, Thaddaeus; Lorenzini, Theo; Stock, Sophia; Mueller, Philipp Jie; Doerr, Janina; Seifert, Matthias; Cadilha, Bruno L.; Brabenec, Ruben; Roeder, Natalie; Rataj, Felicitas; Nueesch, Manuel; Modemann, Franziska; Wellbrock, Jasmin; Fiedler, Walter; Kellner, Christian; Beltran, Eduardo; Herold, Tobias; Paquet, Dominik; Jeremias, Irmela; von Baumgarten, Louisa; Endres, Stefan; Subklewe, Marion; Marr, Carsten und Kobold, Sebastian (2023): Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia. In: Nature Biotechnology, Bd. 41, Nr. 11: 1618-+

Abstract

A single-cell screening approach identifies targets for CAR-T cells in 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198