Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias
Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias
Citació
- Guerrero-Murillo M, Rill-Hinarejos A, Trincado JL, Bataller A, Ortiz-Maldonado V, Benítez-Ribas D, et al. Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias. Cell Rep Med. 2024 Nov 19;5(11):101803. DOI: 10.1016/j.xcrm.2024.101803
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Resum
The impact of phenotypic, clonal, and functional heterogeneity of chimeric antigen receptor (CAR)-T cells on clinical outcome remains understudied. Here, we integrate clonal kinetics with transcriptomic heterogeneity resolved by single-cell omics to interrogate cellular dynamics of non-transduced (CARneg) and transduced (CARpos) T cells, in the infusion product (IP) and at the CAR-T cell expansion peak in five B cell acute lymphoblastic leukemia (B-ALL) patients treated with CD19CAR-T cells (varni-cel). We identify significant differences in cellular dynamics in response to therapy. CARpos T cells at IP of complete response patients exhibit a significantly higher CD4:CD8 ratio, validated in a larger cohort B-ALL patients (n = 47). Conversely, at the expansion peak, there is a clonal expansion of CD8+ effector memory and cytotoxic T cells. Cytotoxic CARpos γδ-T cells expansion correlates with treatment efficacy validated in a cohort of B-ALL (n = 18) and diffuse large B cell lymphoma (DLBCL) patients (n = 58). Our data provide insights into the complexity of T cell responses following CAR-T cell therapy and suggest drivers of immunotherapy response.