Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy

CD19-CAR-T cells are a major therapy for relapsed/refractory B-cell malignancies, yet ~50% of patients relapse after infusion. Clinical data suggest that tisa-cel treatment is associated with higher rates of CD19 mutation than axi-cel, though direct comparisons have been lacking. Although both products target the FMC63 epitope, they employ different structures of hinge/transmembrane/costimulatory domains (CD8α/CD8α/4-1BB in tisa-cel, CD28/CD28/CD28 in axi-cel). Here, we show that CAR structure is a critical determinant of CD19 loss in tumor B cells. Specifically, repeated exposure to CD19–4-1BB-based CAR-T cells, but not CD19–CD28-based counterparts, drives FMC63-epitope and total CD19 protein loss. Consistent with clinical observations, resistance to CD19–4-1BB-based treatment is associated with aberrant splicing, loss of heterozygosity, and frameshift/missense mutations in CD19 in exons encoding the FMC63 epitope. Mathematical modeling indicates that the failure of CD19–4-1BB-based CAR-T cells to eliminate CD19 low cells, unlike CD28-based CARs, promotes the expansion of resistant populations. These results suggest that optimizing recognition of CD19 low cells could prevent the emergence of resistant clones and reduce relapse rates. We also show that commonly used diagnostic anti-CD19 monoclonal antibodies detect epitopes distinct from FMC63 and may therefore give misleading CD19-positive results, underscoring the need for FMC63-specific assessment to guide diagnostic and therapeutic decisions.

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Publication Details

Journal
Leukemia
Published
2026-08-27
DOI
https://doi.org/10.1038/s41375-026-03081-3
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
0.00

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article

Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy

Pablo Menéndez, Daria Owczarek, Jacinta Davis, Sébastien Wälchli et al.
Leukemia
CAR-T cell therapy research
article

Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy

Pablo Menéndez, Daria Owczarek, Jacinta Davis, Sébastien Wälchli, Víctor Galán‐Gómez, Pablo Bousquets‐Muñoz, Antonio Pérez‐Martínez, Agnieszka Graczyk‐Jarzynka, Monika Pępek, Anna Szumera‐Ciećkiewicz, Ana Gutiérrez‐Fernández, Klaudyna Fidyt, Jordi Minguillón, Marta Krawczyk, Emmanuelle Benard, Magdalena Winiarska, Andrei Thomas‐Tikhonenko, Tomasz Winiarski, Narcís Fernández‐Fuentes, Xosé S. Puente, Pablo Sanz-Galarreta, Víctor M. Pérez-García, Adela Escudero López, Elisa Izquierdo Delgado
article en

Abstract

CD19-CAR-T cells are a major therapy for relapsed/refractory B-cell malignancies, yet ~50% of patients relapse after infusion. Clinical data suggest that tisa-cel treatment is associated with higher rates of CD19 mutation than axi-cel, though direct comparisons have been lacking. Although both products target the FMC63 epitope, they employ different structures of hinge/transmembrane/costimulatory domains (CD8α/CD8α/4-1BB in tisa-cel, CD28/CD28/CD28 in axi-cel). Here, we show that CAR structure is a critical determinant of CD19 loss in tumor B cells. Specifically, repeated exposure to CD19–4-1BB-based CAR-T cells, but not CD19–CD28-based counterparts, drives FMC63-epitope and total CD19 protein loss. Consistent with clinical observations, resistance to CD19–4-1BB-based treatment is associated with aberrant splicing, loss of heterozygosity, and frameshift/missense mutations in CD19 in exons encoding the FMC63 epitope. Mathematical modeling indicates that the failure of CD19–4-1BB-based CAR-T cells to eliminate CD19 low cells, unlike CD28-based CARs, promotes the expansion of resistant populations. These results suggest that optimizing recognition of CD19 low cells could prevent the emergence of resistant clones and reduce relapse rates. We also show that commonly used diagnostic anti-CD19 monoclonal antibodies detect epitopes distinct from FMC63 and may therefore give misleading CD19-positive results, underscoring the need for FMC63-specific assessment to guide diagnostic and therapeutic decisions.

Leukemia
Warsaw University of Technology (PL), Institució Catalana de Recerca i Estudis Avançats (ES), Oslo University Hospital (NO), Children's Hospital of Philadelphia (US), Universidad de Oviedo (ES), Medical University of Warsaw (PL), Hospital Universitario La Paz (ES), Josep Carreras Leukaemia Research Institute (ES), Spanish National Cancer Research Centre (ES), Red de Investigación en Sida (ES), Hospital La Paz Institute for Health Research (ES), Unidades Centrales Científico-Técnicas (ES), National Institute of Oncology (HU), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Mossakowski Medical Research Institute, Polish Academy of Sciences (PL), Centro de Investigación Biomédica en Red de Cáncer (ES), Universidad Autónoma de Madrid (ES), Universitat de Barcelona (ES), University of Castilla-La Mancha (ES), University of Pennsylvania (US), University of Rzeszów (PL), Polish Academy of Sciences (PL)
Emerson Collective, European Commission, Ministerio de Ciencia e Innovación, Uniwersytet Łódzki, Narodowa Agencja Wymiany Akademickiej, H2020 Marie Skłodowska-Curie Actions
Good health and well-being
Openalex Percentile: Top 14%
CAR-T cell therapy research
DOIOpen Access PDFOpenAlex
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