CAR T cell–mediated bone marrow inflammation causes hematotoxicity and favors clonal hematopoiesis
Although chimeric antigen receptor (CAR) T cells have shown excellent results in treating hematological malignancies, they also cause side effects. Patients treated with CAR T cells experience persistent cytopenia or hematotox. Here, using a fully immunocompetent mouse model, we recapitulated hematotox and demonstrated that a lymphodepleting regimen alone was insufficient to induce hematotox and required CAR T cell injection. Analysis of bone marrow (BM) samples from patients experiencing hematotox revealed a correlation between BM CAR T cells and hematotox severity. CAR T cells exhibited an activated program, leading to intense inflammation. In addition, we observed a high rate of clonal hematopoiesis in our patient cohort and the emergence of distinct hematopoietic clones in the months after CAR T cell injection. Our study provides insights into the pathophysiology of hematotox and highlights the need for long-term follow-up studies to determine the relevance of this intense BM inflammation in clonal selection.
Authors
- Arnaud Pagès (ORCID: https://orcid.org/0000-0002-2337-8693)
- Myriam Ben Khelil (ORCID: https://orcid.org/0000-0003-4290-4262)
- Stéphane de Botton (ORCID: https://orcid.org/0000-0002-8126-4942)
- Wassila Rahali
- Vincent Ribrag (ORCID: https://orcid.org/0000-0002-5221-353X)
- Iléana Antony‐Debré (ORCID: https://orcid.org/0000-0002-1911-146X)
- Véronique Vergé (ORCID: https://orcid.org/0000-0002-3233-5978)
- Christophe Marzac (ORCID: https://orcid.org/0000-0001-5065-0376)
- Camille Bigenwald (ORCID: https://orcid.org/0000-0003-2714-2087)
- Laurie Menger (ORCID: https://orcid.org/0000-0003-0949-6607)
- Ahmadreza Arbab (ORCID: https://orcid.org/0000-0002-7015-0448)
- Marine Aglave (ORCID: https://orcid.org/0000-0003-3109-8904)
- Janesa Srikanthan
- Cristina Castilla Llorente
- Jean-Baptiste Micol
- Jessica Rengassamy
- Roula Amine-Hneineh
- Rémy Jélin
- Paul-Auguste Goutebroze
- Laura Marcos Kovandzic
Institutions
- Inserm (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Bicêtre Hospital (FR)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1126/scitranslmed.adu9790
- Citations
- 2
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Danish Cancer Society Research Center
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Institut National Du Cancer
- Institut Gustave-Roussy
- Direction Générale de l’offre de Soins