Revolutionizing CAR T-cell Therapy: Enhancing Activity and Persistence of CAR T-cell by Developing a CAR-Enhancer Platform

Project Summary Chimeric Antigen Receptor (CAR) T-cell therapy has achieved notable success in treating various blood-borne malignancies, with six FDA-approved therapies to date, including four targeting the CD19 protein and two targeting the B-cell maturation antigen (BCMA). BCMA CAR T-cell therapy has particularly shown promise against multiple myeloma, even in patients with extramedullary lesions. However, a significant challenge remains: the durability of response, as most patients experience relapse, correlated with the disappearance of CAR T-cells from circulation. Enhancing the effector function and persistence of CAR T-cells is crucial to overcoming these obstacles. The CAR-Enhancer platform proposes a novel approach to augment the functionality and longevity of CAR T- cells by promoting the development of memory CAR T-cells. Leveraging a protein-driven mechanism, CAR- Enhancer obviates the need for specific engineering of CAR T cells, making it universally compatible and significantly broadening its therapeutic application. With compelling preclinical results, this platform is poised to revolutionize CAR T-cell therapy, potentially saving lives and advancing the field. The project’s specific aims are crafted to transition the CAR-Enhancer platform from preclinical development to clinical application efficiently and effectively. The first aim concentrates on optimizing dosing and timing for CAR-Enhancer administration in a Phase I clinical trial to enhance post-infusion efficacy. The second aim is to establish a scalable manufacturing process, ensuring the capability to meet clinical and commercial demands. The third aim assesses the pharmacokinetics and toxicity profile of CAR-Enhancer in both immunocompetent mice and non-human primates, providing critical safety data for regulatory approval. This initiative aims to expand the reach of CAR T-cell therapies, fostering improved outcomes for a wider range of patients with blood cancers.