PuSH - Publikationsserver des Helmholtz Zentrums München: The role of single cell transcriptomics for efficacy and toxicity profiling of chimeric antigen receptor (CAR) T cell therapies.

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Thomas, M. ; Brabenec, R. ; Gregor, L.* ; Andreu-Sanz, D.* ; Carlini, E.* ; Müller, P.J.* ; Gottschlich, A.* ; Simnica, D.* ; Kobold, S. ; Marr, C.

The role of single cell transcriptomics for efficacy and toxicity profiling of chimeric antigen receptor (CAR) T cell therapies.

Comput. Biol. Med. 192:110332 (2025)

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CAR T cells are genetically modified T cells that target specific epitopes. CAR T cell therapy has proven effective in difficult-to-treat B cell cancers and is now expanding into hematology and solid tumors. To date, approved CAR therapies target only two specific epitopes on cancer cells. Identifying more suitable targets is challenged by the lack of truly cancer-specific structures and the potential for on-target off-tumor toxicity. We analyzed gene expression of potential targets in single-cell data from cancer and healthy tissues. Because safety and efficacy can ultimately only be defined clinically, we selected approved and investigational targets for which clinical trail data are available. We generated atlases using >300,000 cells from 48 patients with follicular lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia, and integrated over 3 million cells from 35 healthy tissues, harmonizing datasets from over 300 donors. To contextualize findings, we compared target expression patterns with outcome data from clinical trials, linking target profiles to efficacy and toxicity, and ranked 15 investigational targets based on their similarity to approved ones. Target expression did not significantly correlate with reported clinical toxicities in patients undergoing therapy. This may be attributed to the intricate interplay of patient-specific variables, the limited amount of metadata, and the complexity underlying toxicity. Nevertheless, our study serves as a resource for retrospective and prospective target evaluation to improve the safety and efficacy of CAR therapies.

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