A distinct CAR-T cell phenotype mediates therapeutic response at limited doses

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.

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Publication Details

Journal
Nature Communications
Published
2026-07-29
DOI
https://doi.org/10.1038/s41467-026-76068-4
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
0.00

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article

A distinct CAR-T cell phenotype mediates therapeutic response at limited doses

Maria‐Luisa Schubert, Daniel Hübschmann, Arik Horne, Michael Schmitt et al.
Nature Communications
CAR-T cell therapy research
article

A distinct CAR-T cell phenotype mediates therapeutic response at limited doses

Maria‐Luisa Schubert, Daniel Hübschmann, Arik Horne, Michael Schmitt, Patrick Derigs, Jan Krönke, Schayan Yousefian, Carsten Müller‐Tidow, Ulrich Keller, Simon Haas, Sarah Gräßle, Caroline Röthemeier, Anna Rita Minafra, A Schmitt, Franziska Pupp, Uta E. Höpken, Peter Dreger, Antonia Busse, Julian Liebaert, Uta M. Demel
article en

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.

Nature CommunicationsVol. 17(1)
Queen Mary University of London (GB), German Cancer Research Center (DE), Max Delbrück Center (DE), Heidelberg University (DE), Universitätsmedizin Greifswald (DE), University Hospital Heidelberg (DE), Humboldt-Universität zu Berlin (DE), German Cancer Society (DE), National Center for Tumor Diseases (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Charité - Universitätsmedizin Berlin (DE)
Deutsches Krebsforschungszentrum, Joachim Herz Stiftung, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutschen Konsortium für Translationale Krebsforschung
Openalex Percentile: Top 12%
CAR-T cell therapy research
DOIOpen Access PDFOpenAlex
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