Nature cancer · 2024
Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma.
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Rade Michael, Grieb Nora, Weiss Ronald, Sia Jaren, Fischer Luise, Born Patrick, Boldt Andreas, Fricke Stephan, Franz Paul, Scolnick Jonathan, Venkatraman Lakshmi, Xu Stacy, Kloetzer Christina, Heyn Simone, Kubasch Anne Sophie, Baber Ronny, Wang Song Yau, Bach Enrica, Hoffmann Sandra, Ussmann Jule, Schetschorke Birthe, Hell Saskia, Schwind Sebastian, Metzeler Klaus H, Herling Marco, Jentzsch Madlen, Franke Georg-Nikolaus, Sack Ulrich, Köhl Ulrike, Platzbecker Uwe, Reiche Kristin, Vucinic Vladan, Merz Maximilian
Аннотация
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.