%0 Journal Article %1 rade_single-cell_2024 %A Rade, Michael %A Grieb, Nora %A Weiss, Ronald %A Sia, Jaren %A Fischer, Luise %A Born, Patrick %A Boldt, Andreas %A Fricke, Stephan %A Franz, Paul %A Scolnick, Jonathan %A Venkatraman, Lakshmi %A Xu, Stacy %A Kloetzer, Christina %A Heyn, Simone %A Kubasch, Anne Sophie %A Baber, Ronny %A Wang, Song Yau %A Bach, Enrica %A Hoffmann, Sandra %A Ussmann, Jule %A Schetschorke, Birthe %A Hell, Saskia %A Schwind, Sebastian %A Metzeler, Klaus H. %A Herling, Marco %A Jentzsch, Madlen %A Franke, Georg-Nikolaus %A Sack, Ulrich %A Köhl, Ulrike %A Platzbecker, Uwe %A Reiche, Kristin %A Vucinic, Vladan %A Merz, Maximilian %D 2024 %J Nature Cancer %K topic_lifescience %R 10.1038/s43018-024-00763-8 %T Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma %U https://doi.org/10.1038/s43018-024-00763-8 %X 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.

@article{rade_single-cell_2024, 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.}, added-at = {2024-09-10T10:41:24.000+0200}, author = {Rade, Michael and Grieb, Nora and Weiss, Ronald and Sia, Jaren and Fischer, Luise and Born, Patrick and Boldt, Andreas and Fricke, Stephan and Franz, Paul and Scolnick, Jonathan and Venkatraman, Lakshmi and Xu, Stacy and Kloetzer, Christina and Heyn, Simone and Kubasch, Anne Sophie and Baber, Ronny and Wang, Song Yau and Bach, Enrica and Hoffmann, Sandra and Ussmann, Jule and Schetschorke, Birthe and Hell, Saskia and Schwind, Sebastian and Metzeler, Klaus H. and Herling, Marco and Jentzsch, Madlen and Franke, Georg-Nikolaus and Sack, Ulrich and Köhl, Ulrike and Platzbecker, Uwe and Reiche, Kristin and Vucinic, Vladan and Merz, Maximilian}, biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/227fde25ecac88201afd5f57bd3f0fe4a/scadsfct}, doi = {10.1038/s43018-024-00763-8}, interhash = {ad45ec77985647272376ecf34965236f}, intrahash = {27fde25ecac88201afd5f57bd3f0fe4a}, issn = {2662-1347}, journal = {Nature Cancer}, keywords = {topic_lifescience}, month = apr, timestamp = {2024-11-22T15:48:27.000+0100}, title = {Single-cell multiomic dissection of response and resistance to chimeric antigen receptor {T} cells against {BCMA} in relapsed multiple myeloma}, url = {https://doi.org/10.1038/s43018-024-00763-8}, year = 2024 }