Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias
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 (CAR<sup>neg</sup>) and transduced (CAR<sup>pos</sup>) 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. CAR<sup>pos</sup> 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<sup>+</sup> effector memory and cytotoxic T cells. Cytotoxic CAR<sup>pos</sup> 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.
Authors
- Pablo Menéndez (ORCID: https://orcid.org/0000-0001-9372-1007)
- Álvaro Urbano-Ispizúa (ORCID: https://orcid.org/0000-0002-7529-9399)
- Julio Delgado (ORCID: https://orcid.org/0000-0002-5157-4376)
- Susana Rives (ORCID: https://orcid.org/0000-0002-5658-1831)
- Mercedes Guerrero-Murillo (ORCID: https://orcid.org/0000-0002-5556-2460)
- Marta Español‐Rego (ORCID: https://orcid.org/0000-0001-5497-2276)
- Álex Bataller (ORCID: https://orcid.org/0000-0002-6085-2745)
- Alejandro Martı́n (ORCID: https://orcid.org/0000-0001-6330-1028)
- Valentín Ortiz‐Maldonado (ORCID: https://orcid.org/0000-0003-4699-6862)
- Clara Bueno (ORCID: https://orcid.org/0000-0003-1442-6216)
- Europa Azucena González‐Navarro (ORCID: https://orcid.org/0000-0003-3310-5557)
- Manel Juan (ORCID: https://orcid.org/0000-0002-3064-1648)
- Holger Heyn (ORCID: https://orcid.org/0000-0002-3276-1889)
- Elisabetta Mereu (ORCID: https://orcid.org/0000-0001-6101-8472)
- Lourdes Martín‐Martín (ORCID: https://orcid.org/0000-0001-7996-570X)
- Juan L. Trincado (ORCID: https://orcid.org/0000-0001-5363-3774)
- Núria Martínez‐Cibrián (ORCID: https://orcid.org/0000-0002-8688-1202)
- Daniel Benítez‐Ribas (ORCID: https://orcid.org/0000-0002-2346-5324)
- Doménica Marchese (ORCID: https://orcid.org/0000-0002-3036-4580)
- Alberto Órfão (ORCID: https://orcid.org/0000-0002-0007-7230)
- Aina Rill-Hinarejos
Institutions
- Universidad de Salamanca (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Hospital Clínic de Barcelona (ES)
- Instituto de Investigación Biomédica de Salamanca (ES)
- Centre for Genomic Regulation (ES)
- Centro de Investigación del Cáncer (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101803
- Citations
- 8
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.26
Funders
- Centres de Recerca de Catalunya
- European Commission
- Translation Centre for the Bodies of the European Union
- Generalitat de Catalunya
- Horizon 2020 Framework Programme
- Agencia Estatal de Investigación