Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy
Year: 2026
Type: article
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.
Source: Leukemia
Authors: Marta Krawczyk, Klaudyna Fidyt, Narcis Fernandez-Fuentes, Tomasz Winiarski, Monika Pepek, Pablo Bousquets-Muñoz, Xose S. Puente, Ana Gutiérrez-Fernández, Jacinta Davis, Daria Owczarek, Agnieszka Graczyk-Jarzynka, Pablo Sanz-Galarreta, Pablo Menendez, Anna Szumera-Ciećkiewicz, Emmanuelle Benard, Sébastien Wälchli, Andrei Thomas-Tikhonenko, Víctor M. Pérez-García, Víctor Galán-Gómez, Adela Escudero López, Elisa Izquierdo Delgado, Jordi Minguillón, Antonio Pérez-Martínez, Magdalena Winiarska
Institutions: Medical University of Warsaw, Mossakowski Medical Research Institute, Polish Academy of Sciences, Polish Academy of Sciences, Instituto de Salud Carlos III, Josep Carreras Leukaemia Research Institute, Warsaw University of Technology, University of Rzeszów, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Cáncer, Children's Hospital of Philadelphia, The Maria Sklodowska-Curie National Research Institute of Oncology, University of Castilla-La Mancha, Institució Catalana de Recerca i Estudis Avançats, Institut de Recerca Sant Joan de Déu, Universitat de Barcelona, Oslo University Hospital, University of Pennsylvania, Hospital Universitario La Paz, Spanish National Cancer Research Centre, Hospital La Paz Institute for Health Research, Centre for Biomedical Network Research on Rare Diseases, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
Awards: G3428740749, G745419941
OpenAlex ID: W7204441521