Bioengineered immunocompetent preclinical trial-on-chip tool enables screening of CAR T cell therapy for leukaemia
Year: 2025
Type: article
Abstract: Chimeric antigen receptor (CAR) T cell immunotherapy is promising for treatment of blood cancers; however, clinical benefits remain unpredictable, necessitating development of optimal CAR T cell products. Unfortunately, current preclinical evaluation platforms are inadequate due to their limited physiological relevance to humans. We herein engineered an organotypic immunocompetent chip that recapitulates microarchitectural and pathophysiological characteristics of human leukemia bone marrow stromal and immune niches for CAR T cell therapy modeling. This leukemia chip empowered real-time spatiotemporal monitoring of CAR T cell functionality, including T cell extravasation, recognition of leukemia, immune activation, cytotoxicity, and killing. We next on-chip modelled and mapped different responses post CAR T cell therapy, i.e., remission, resistance, and relapse as observed clinically and identify factors that potentially drive therapeutic failure. Finally, we developed a matrix-based analytical and integrative index to demarcate functional performance of CAR T cells with different CAR designs and generations produced from healthy donors and patients. Together, our chip introduces an enabling '(pre-)clinical-trial-on-chip' tool for CAR T cell development, which may translate to personalized therapies and improved clinical decision-making.
Source: Nature Biomedical Engineering
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Cancer Research Institute, American Society of Hematology, Alex's Lemonade Stand Foundation for Childhood Cancer, Pride Foundation, Leukemia and Lymphoma Society, St. Baldrick's Foundation, AABB, Cancer League of Colorado, Curing Kids Cancer, Children’s Oncology Group, National Institutes of Health, Directorate for Engineering, National Blood Foundation, National Cancer Institute, National Institute of General Medical Sciences, Division of Chemical, Bioengineering, Environmental, and Transport Systems, Congressionally Directed Medical Research Programs, DOD Peer Reviewed Cancer Research Program
Awards: G1052959513, G1510259540, G1649602187, G1734361364, G2035148323, G2182617325, G2788690614, Dissecting the Functional Role of Monocytes in B-cell Acute Lymphoblastic Leukemia Survival, G3635291333, G3845734265, G391483825, Mechanisms of enhancer regulation in leukemia, Innovative Approaches to Enhance Chimeric Antigen Receptor (CAR) T-Cell Potency Using Quiescent T Cells, G4507048572, Targeting an RNA Binding Protein Network in Acute Myeloid Leukemia, G4943742837, G5665494269, G5733525189, Dynamic 3D chromatin remodeling in acute leukemia - Resubmission - 1, G6459979171, G6688045770, INNOVATIVE APPROACHES TO ENHANCE CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL POTENCY USING QUIESCENT T CELLS, G7145547518, G7844792036, Dissecting and engineering CAR T-cell function for optimized Immunotherapy, G8194154130, G8619616150, G9000046396, G9000252552, The impact of changes in chromatin architecture on cancer phenotypes and tumor progression
OpenAlex ID: W4411900499