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Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study

Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalatin...

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Main Authors: Derigs, Patrick (Author) , Schubert, Maria-Luisa (Author) , Dreger, Peter (Author) , Schmitt, Anita (Author) , Yousefian, Schayan (Author) , Haas, Simon (Author) , Röthemeier, Caroline (Author) , Neuber, Brigitte (Author) , Hückelhoven-Krauss, Angela (Author) , Brüggemann, Monika (Author) , Bernhard, Helga (Author) , Kobbe, Guido (Author) , Lindemann, Albrecht (Author) , Rummel, Mathias (Author) , Michels, Birgit (Author) , Korell, Felix (Author) , Ho, Anthony Dick (Author) , Müller-Tidow, Carsten (Author) , Schmitt, Michael (Author)
Format: Article (Journal)
Language:English
Published: 27 August 2024
In: Leukemia
Year: 2024, Volume: 38, Issue: 11, Pages: 2419-2428
ISSN:1476-5551
DOI:10.1038/s41375-024-02392-7
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41375-024-02392-7
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41375-024-02392-7
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Author Notes:Patrick Derigs, Maria-Luisa Schubert, Peter Dreger, Anita Schmitt, Schayan Yousefian, Simon Haas, Caroline Röthemeier, Brigitte Neuber, Angela Hückelhoven-Krauss, Monika Brüggemann, Helga Bernhard, Guido Kobbe, Albrecht Lindemann, Mathias Rummel, Birgit Michels, Felix Korell, Anthony D. Ho, Carsten Müller-Tidow and Michael Schmitt
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Summary:Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.
Item Description:Gesehen am 05.09.2025
Physical Description:Online Resource
ISSN:1476-5551
DOI:10.1038/s41375-024-02392-7

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