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| Item Type: | Article |
|---|---|
| Title: | A distinct CAR-T cell phenotype mediates therapeutic response at limited doses |
| Creators: |
Yousefian, Schayan  ORCID: https://orcid.org/0000-0003-0902-0369, Schubert, Maria-Luisa, Minafra, Anna Rita, Derigs, Patrick ORCID: https://orcid.org/0000-0002-4670-8851, Gräßle, Sarah ORCID: https://orcid.org/0000-0002-5260-6392, Horne, Arik ORCID: https://orcid.org/0000-0002-4209-4573, Demel, Uta M. ORCID: https://orcid.org/0000-0002-6480-4185, Liebaert, Julian ORCID: https://orcid.org/0009-0009-7547-1222, Röthemeier, Caroline, Pupp, Franziska ORCID: https://orcid.org/0009-0009-4883-3275, Höpken, Uta E. ORCID: https://orcid.org/0000-0002-0776-4893, Krönke, Jan ORCID: https://orcid.org/0000-0002-4649-0506, Busse, Antonia ORCID: https://orcid.org/0000-0002-3470-6947, Keller, Ulrich ORCID: https://orcid.org/0000-0002-8485-1958, Schmitt, Anita, Hübschmann, Daniel ORCID: https://orcid.org/0000-0002-6041-7049, Müller-Tidow, Carsten ORCID: https://orcid.org/0000-0002-7166-5232, Dreger, Peter, Schmitt, Michael ORCID: https://orcid.org/0000-0002-1579-1509 and Haas, Simon ORCID: https://orcid.org/0000-0001-9227-2051
|
| Abstract: | Chimeric antigen receptor (CAR) T-cell therapies are typically administered at high doses to maximize durable clinical responses. However, manufacturing constraints can limit the production of sufficient cells to achieve the intended dose. Although some patients experience durable responses after receiving lower CAR-T cell doses, the mechanisms underlying efficacy at these limited cell numbers remain poorly understood. To address this, we performed deep phenotyping of anti-CD19 CAR-T cell products and their corresponding leukapheresis starting materials from a phase I/II dose-escalation trial. We also report the primary and secondary clinical outcomes of the diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma cohorts of the HD-CAR-1 basket trial (NCT03676504; EudraCT 2016-004808-60). Patients responding to low-dose CAR-T therapy showed dose-dependent enrichment of functional effector and effector memory-like CAR-T cells. The absolute number of these cells emerged as a robust biomarker of therapeutic response, valid across dose levels and CAR-T targets. Effective low-dose products were associated with high T-cell numbers and T-cell-supportive myeloid states in leukapheresis materials, whereas regulatory myeloid states promoted dysfunctional CAR-T cells and treatment failure. Our study provides insights into the phenotype, mechanisms, and biomarkers of CAR-T cells that drive therapeutic responses at low doses, with medical and socioeconomic implications. |
| Keywords: | Adoptive Immunotherapy, CD19 Antigens, Chimeric Antigen Receptors, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Leukapheresis, Mantle-Cell Lymphoma, Phenotype, T-Cell Antigen Receptors, T-Lymphocytes, Treatment Outcome |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 17 |
| Number: | 1 |
| Page Range: | 7589 |
| Date: | 29 July 2026 |
| Official Publication: | https://doi.org/10.1038/s41467-026-76068-4 |
| PubMed: | View item in PubMed |
| Related to: |
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