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Updated: Jul 31, 2025
Author Spotlight: Enhancing CAR-T Cell Function in Syngeneic Tumor Models
Published on: February 2, 2024
A bioengineered immunocompetent human leukemia chip for preclinical screening of CAR T cell immunotherapy
Chao Ma1,2, Huishu Wang1, Lunan Liu1
1Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY 11201, USA.
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.
Insights
A novel organotypic chip models human leukemia bone marrow niches to evaluate chimeric antigen receptor (CAR) T cell therapy. This tool predicts CAR T cell efficacy and identifies factors contributing to treatment failure in blood cancers.
Area of Science:
- Biomedical Engineering
- Immunotherapy
- Oncology
Background:
- Chimeric antigen receptor (CAR) T cell immunotherapy shows promise for blood cancers but clinical outcomes are unpredictable.
- Current preclinical models lack the physiological relevance needed to optimize CAR T cell products.
Purpose of the Study:
- To engineer an organotypic immunocompetent chip that mimics human leukemia bone marrow microenvironment for CAR T cell therapy modeling.
- To enable real-time monitoring of CAR T cell functions and model clinical responses like remission, resistance, and relapse.
Main Methods:
- Developed an organotypic chip recapitulating human leukemia bone marrow stromal and immune niches.
- Utilized the chip for spatiotemporal monitoring of CAR T cell extravasation, leukemia recognition, immune activation, and cytotoxicity.
- Modeled on-chip CAR T cell therapy responses, including remission, resistance, and relapse.
Main Results:
- The leukemia chip allowed real-time monitoring of CAR T cell functionality and interactions within a human-like microenvironment.
- Successfully modeled clinical outcomes of CAR T cell therapy, identifying factors associated with therapeutic failure.
- Developed a matrix-based index to assess the functional performance of CAR T cells from different designs and patient groups.
Conclusions:
- The engineered chip serves as a '(pre-)clinical-trial-on-chip' tool for advancing CAR T cell therapy development.
- This platform can aid in personalizing CAR T cell treatments and improving clinical decision-making for blood cancer patients.
