{"title":"CAR T cell–mediated bone marrow inflammation causes hematotoxicity and favors clonal hematopoiesis","authors":"Myriam Ben Khelil, Ahmadreza Arbab, Janesa Srikanthan, Laura Marcos Kovandzic, Véronique Vergé, Arnaud Pagès, Jessica Rengassamy, Roula Amine-Hneineh, Marine Aglave, Rémy Jelin, Vincent Ribrag, Wassila Rahali, Paul-Auguste Goutebroze, Stéphane de Botton, Laurie Menger, Ileana Antony-Debré, Jean-Baptiste Micol, Christophe Marzac, Cristina Castilla Llorente, Camille Bigenwald","doi":"10.1126/scitranslmed.adu9790","DOIUrl":null,"url":null,"abstract":"<div >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.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adu9790","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.