To find markers of response and non-response to BCMA-targeted CAR T cell therapy, Rade and Grieb et al. applied longitudinal, single-cell multiomics on peripheral blood and bone marrow before and after CAR T cell infusion in heavily pretreated patients with relapsed/refractory MM. Differences between responders (5 CR) and non-responders (5 with poor outcomes) were identified at apheresis, prior to CAR T cell infusion. Non-responders had a suppressive microenvironment with increased CD39+ monocytes and fewer and functionally impaired CD8+ T cells and NK cells. After therapy, hyperexpanded CAR T cell clones had an exhausted PD-1+ phenotype compared to low/intermediate clones.
Contributed by Katherine Turner
ABSTRACT: Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8(+) T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma.
Author Info: (1) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. (2) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, L
Author Info: (1) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. (2) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. Innovation Center Computer Assisted Surgery, University Hospital of Leipzig, Leipzig, Germany. (3) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (4) Singleron Biotechnologies, Cologne, Germany. (5) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (6) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (7) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (8) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (9) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (10) Singleron Biotechnologies, Cologne, Germany. (11) Singleron Biotechnologies, Cologne, Germany. (12) Singleron Biotechnologies, Cologne, Germany. (13) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (14) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (15) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (16) Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany. Leipzig Medical Biobank, University Leipzig, Leipzig, Germany. (17) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (18) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (19) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (20) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (21) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (22) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (23) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (24) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (25) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (26) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (27) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (28) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (29) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (30) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (31) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Dresden, Leipzig, Germany. (32) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (33) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. maximilian.merz@medizin.uni-leipzig.de.
