Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias

Guerrero Murillo, Mercedes; Marchese, Domenica, 1986-; Heyn, Holger; Menéndez, Pablo

Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias

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dc.contributor.author Guerrero Murillo, Mercedes
dc.contributor.author Marchese, Domenica, 1986-
dc.contributor.author Heyn, Holger
dc.contributor.author Menéndez, Pablo
dc.date.accessioned 2025-01-22T07:23:45Z
dc.date.available 2025-01-22T07:23:45Z
dc.date.issued 2024
dc.description.abstract 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.
dc.description.sponsorship Research in P.M./C.B. laboratory was supported by CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for core support, the European Research Council grants (ERC-PoC-957466, ERC-PoC-101100665), H2020 (101057250-CANCERNA), the Fight Kids Cancer Foundation (Cure2MLL project), the Spanish Research Agency (AEI) (PID2022-142966OB-I00 funded by MCIN/AEI/10.13039/501100011033; FEDER Funds; CPP2021-008508, CPP2021-008676, and CPP2022-009759 funded by MICIU/AEI/10.13039/501100011033; and the European Union NextGenerationEU/PRTR), Ayudas Merck de Investigación from Health Merck Foundation, the Spanish Association Against Cancer (AECC, PRYGN234975MENE), and the ISCIII-RICORS within the Next Generation EU program (Plan de Recuperación, Transformación y Resilencia). Additional funding was provided to C.B. by AECC (PRYGN211192BUEN), the Uno Entre Cien Mil Foundation, AIE (MINECO PLE2021-007518), Deutsche José Carreras Leukämie-Stiftung (DJCLS/02R/2023), and the Health Institute Carlos III (ISCIII/FEDER, PI20/00822 and PI24/00763).
dc.format.mimetype application/pdf
dc.identifier.citation 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
dc.identifier.doi http://dx.doi.org/10.1016/j.xcrm.2024.101803
dc.identifier.issn 2666-3791
dc.identifier.uri http://hdl.handle.net/10230/69230
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Rep Med. 2024 Nov 19;5(11):101803
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/957466
dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101100665
dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101057250
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-142966OB-I00
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.other Cèl·lules B--Tumors
dc.title Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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