Gottschlich, Thomas, and Grünmeier et al. rigorously analyzed publicly available scRNAseq data from 15 patients with AML, and identified CSF1R and CD86 as potential CAR-T cell targets. CSF1R and CD86 were preferentially expressed on malignant HSPC-like cells compared to healthy HSPCs, and off-tumor expression was restricted to certain monocytic cell populations, including microglia for CSF1R. Anti-mouse and -human CAR-T cells efficiently lysed AML cells in vitro and in in vivo PDX models, with minimal off-target toxicity. CSF1R-CAR-T showed superior discrimination of healthy hematopoietic cells compared to CD33-CAR-T, and didn’t lyse microglia cells in physiological E:T ratios ex vivo.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. Bavarian Cancer Research Center (BZKF)
Author Info: (1) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. Bavarian Cancer Research Center (BZKF), Munich, Germany. Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (2) Institute of AI for Health, Helmholtz Munich, Neuherberg, Germany. School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. (3) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (4) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (5) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (6) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (7) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (8) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (9) Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Munich, German Research Center for Environmental Health (HMGU), Munich, Germany. Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany. (10) Department of Neurology, University Hospital, LMU Munich, Munich, Germany. (11) Department of Neurology, University Hospital, LMU Munich, Munich, Germany. (12) Department of Neurology, University Hospital, LMU Munich, Munich, Germany. (13) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (14) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (15) Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. (16) Institute of Pathology, LMU Munich, Munich, Germany. (17) Institute of Pathology, LMU Munich, Munich, Germany. (18) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (19) Institute of Clinical Neuroimmunology, University Hospital, LMU Munich, Munich, Germany. Biomedical Center (BMC), Faculty of Medicine, LMU Munich, Martinsried, Germany. (20) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (21) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (22) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (23) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (24) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (25) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (26) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (27) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (28) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (29) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (30) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. Institute of AI for Health, Helmholtz Munich, Neuherberg, Germany. (31) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (32) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (33) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. (34) Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Mildred Scheel Cancer Career Center, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf Hamburg, Hamburg, Germany. (35) Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (36) Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (37) Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, Germany. (38) Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Institute of Clinical Neuroimmunology, University Hospital, LMU Munich, Munich, Germany. Biomedical Center (BMC), Faculty of Medicine, LMU Munich, Martinsried, Germany. (39) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (40) Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. (41) Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Munich, German Research Center for Environmental Health (HMGU), Munich, Germany. Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (42) German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Department of Neurosurgery, LMU Munich, Munich, Germany. (43) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Einheit fr Klinische Pharmakologie (EKLiP), Helmholtz Munich, Research Center for Environmental Health (HMGU), Neuherberg, Germany. (44) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (45) Institute of AI for Health, Helmholtz Munich, Neuherberg, Germany. (46) Division of Clinical Pharmacology, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. sebastian.kobold@med.uni-muenchen.de. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. sebastian.kobold@med.uni-muenchen.de. Einheit fr Klinische Pharmakologie (EKLiP), Helmholtz Munich, Research Center for Environmental Health (HMGU), Neuherberg, Germany. sebastian.kobold@med.uni-muenchen.de.
