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 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.
Authors
- Valeriya Dimitrova (ORCID: https://orcid.org/0000-0002-8621-7301)
- Birgit Knoechel (ORCID: https://orcid.org/0000-0002-8040-0535)
- Hannah S. Stuart (ORCID: https://orcid.org/0000-0003-4628-6561)
- Monica Nair
- Klothilda Lim (ORCID: https://orcid.org/0000-0002-9791-6503)
- Kenneth Carl Anderson (ORCID: https://orcid.org/0000-0002-6418-0886)
- Jianlin Liu (ORCID: https://orcid.org/0000-0003-3732-5143)
- Nikhil C. Munshi (ORCID: https://orcid.org/0000-0002-7344-9795)
- Jens G. Lohr (ORCID: https://orcid.org/0000-0003-3486-2445)
- Noopur S Raje (ORCID: https://orcid.org/0000-0003-3066-1275)
- Andrew Jenho Yee (ORCID: https://orcid.org/0000-0003-3623-7491)
- Julia Frede (ORCID: https://orcid.org/0000-0002-4380-9673)
- Claire C. Havig (ORCID: https://orcid.org/0000-0001-5209-4895)
- Praveen Anand (ORCID: https://orcid.org/0000-0002-2478-7042)
- Marc S. Raab (ORCID: https://orcid.org/0000-0003-4181-6922)
- Noori Sotudeh (ORCID: https://orcid.org/0000-0002-1683-7273)
- Shari M. Kaiser (ORCID: https://orcid.org/0009-0003-8337-9123)
- Eugene Y. Cho (ORCID: https://orcid.org/0000-0003-1250-2932)
- Johannes M. Waldschmidt (ORCID: https://orcid.org/0000-0001-5340-1818)
- Caroline R.M. Wiggers (ORCID: https://orcid.org/0000-0001-6633-1468)
- Nathan Martin (ORCID: https://orcid.org/0009-0002-2658-0958)
- Anna Montanaro (ORCID: https://orcid.org/0000-0002-5229-5395)
- Julia C Poller
- Kayleen Shi
- Tushara Vijaykumar
Institutions
- Broad Institute (US)
- University of Parma (IT)
- Harvard University (US)
- University of Utah (US)
- Heidelberg University (DE)
- Huntsman Cancer Institute (US)
- VA Boston Healthcare System (US)
- University Hospital Heidelberg (DE)
- Massachusetts General Hospital (US)
- Bristol-Myers Squibb (United States) (US)
- Dana-Farber Cancer Institute (US)
- Technical University of Munich (DE)
Publication Details
- Journal
- Leukemia
- Published
- 2025-09-19
- DOI
- https://doi.org/10.1038/s41375-025-02766-5
- Citations
- 5
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 5.23