Point-of-care autologous CAR-T cell manufacturing

The successful implementation of chimeric antigen receptor (CAR)-T cell therapies relies on effective cell product manufacturing. This process not only affects the cost, safety and efficacy of the final product but also plays a crucial role in ensuring broader patient access to this innovative treatment. The increasing demand for CAR-T therapies has resulted in shortages due to inadequate manufacturing capacity, partly because of the centralized manufacturing model. Remarkably, approximately 25% of patients with multiple myeloma died while on an eligible CAR-T treatment waitlist. Although “off-the-self” allogeneic CAR-T cells may be manufactured in centralized facilities at a larger scale, this approach is still in the early stages of development with several existing and perhaps unforeseen hurdles. Currently, autologous CAR-T therapies remain the most clinically and regulatory acceptable option for patients. An alternative approach is local manufacturing using automated platforms like CliniMACS Prodigy. These efforts, aimed at democratizing supply, boosting production capacity, simplifying logistics, and reducing turnaround time, encounter numerous hurdles to implement. These barriers arise from the fact that current techniques for CAR-T cell manufacturing are rooted in decades-old methodologies used in research laboratories. The complex process of integrating these methods for large-scale production, even with automation, poses challenges in bioprocessing, engineering, and regulatory compliance. Here we propose an innovative approach, focusing on T cell biology, to overcome these obstacles for point-of-care CAR- T production by leveraging targeted microbubble-based technologies. This system has been applied for T cell selection, activation, and transduction in a conventional preclinical study for CAR-T based therapy. By capitalizing on robust biological activities of the reagents and streamlining the process, we aim to make CAR-T cell production efficient, affordable, and accessible. We will develop a user-friendly kit that enables CAR-T cell production in settings equivalent to those used for hematopoietic stem cell transplantation. The CAR-T cells manufactured by this considerably simplified protocol will undergo standard cell release quality control and be tested in a preclinical mouse model for hematological malignancy. As we progress to Phase II, we will adapt our protocols to manufacture CAR-T cells for treating both hematological malignancies and solid tumors to ensure versatility and relevance across different therapeutic contexts. Overall, the primary goal of this project is to generate high quality point-of-care CAR-T cells by a radically simplified manufacturing process without substantial investment for new staff and infrastructures. When successful, it will drastically lower the manufacturing costs, potentially eliminate “waitlist mortality” and likely alleviate regulatory burdens.