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The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma

While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoin...

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Hauptverfasser: Frede, Julia (VerfasserIn) , Poller, Julia C. (VerfasserIn) , Shi, Kayleen (VerfasserIn) , Stuart, Hannah (VerfasserIn) , Sotudeh, Noori (VerfasserIn) , Havig, Claire (VerfasserIn) , Lim, Klothilda (VerfasserIn) , Wiggers, Caroline R. M. (VerfasserIn) , Cho, Eugene Y. (VerfasserIn) , Vijaykumar, Tushara (VerfasserIn) , Liu, Jianlin (VerfasserIn) , Waldschmidt, Johannes M. (VerfasserIn) , Nair, Monica S. (VerfasserIn) , Anand, Praveen (VerfasserIn) , Dimitrova, Valeriya (VerfasserIn) , Montanaro, Anna (VerfasserIn) , Yee, Andrew J. (VerfasserIn) , Munshi, Nikhil C. (VerfasserIn) , Anderson, Kenneth C. (VerfasserIn) , Martin, Nathan (VerfasserIn) , Kaiser, Shari M. (VerfasserIn) , Raab, Marc-Steffen (VerfasserIn) , Raje, Noopur S. (VerfasserIn) , Knoechel, Birgit (VerfasserIn) , Lohr, Jens G. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 19 September 2025
In: Leukemia
Year: 2025, Jahrgang: 39, Heft: 12, Pages: 3004-3014
ISSN:1476-5551
DOI:10.1038/s41375-025-02766-5
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41375-025-02766-5
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41375-025-02766-5
Volltext
Verfasserangaben:Julia Frede, Julia C. Poller, Kayleen Shi, Hannah Stuart, Noori Sotudeh, Claire Havig, Klothilda Lim, Caroline R. M. Wiggers, Eugene Y. Cho, Tushara Vijaykumar, Jianlin Liu, Johannes M. Waldschmidt, Monica S. Nair, Praveen Anand, Valeriya Dimitrova, Anna Montanaro, Andrew J. Yee, Nikhil C. Munshi, Kenneth C. Anderson, Nathan Martin, Shari M. Kaiser, Marc-Steffen Raab, Noopur S. Raje, Birgit Knoechel, and Jens G. Lohr
Beschreibung
Zusammenfassung:While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8 + T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the ‘mileage’ of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.
Beschreibung:Gesehen am 18.02.2026
Beschreibung:Online Resource
ISSN:1476-5551
DOI:10.1038/s41375-025-02766-5

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