Determinants of Chimeric Antigen Receptor (CAR) T Cell Success: In Vitro and In Vivo Preclinical Assessment.

BACKGROUND/

objectivesChimeric antigen receptor (CAR) T cell therapy has profoundly transformed the cancer treatment landscape, achieving unprecedented clinical success in patients with hematological malignancies. However, challenges such as cytokine release syndrome, neurotoxicity, antigen escape, and limited efficacy in solid tumors remain, underscoring the need for robust preclinical modeling to evaluate novel CAR T cell products.

methodsThis review provides a comprehensive overview of in vitro and in vivo preclinical modeling for CAR T cell functionality and toxicity assessment. We examine traditional experimental approaches and their limitations, discuss emerging technologies, and highlight how these strategies can be integrated to advance future CAR T cell therapies.

resultsIn vitro assays provide insights into efficacy but fail to model trafficking, dynamic immune cell interactions, and complex tumor microenvironments. In vivo mouse models allow for more complex physiological evaluation but are limited by species differences. Next generation platforms, such as patient-derived tumor organoids and organ- or multi-organ-on-a-chip microfluidics are emerging as potential tools to model CAR T cell therapy in physiologically relevant contexts and computational approaches are being increasingly used to develop novel CAR designs and predict patient responses.

conclusionsBy integrating traditional experimental approaches with innovative technologies, the CAR T cell field is poised to generate more clinically relevant and predictive data thereby accelerating the development of safer, more effective, and personalized CAR T cell therapies.