Biomaterial Scaffolds for Ex Vivo and In Situ CAR-T Cell Production

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PROJECT SUMMARY Despite unprecedented clinical success of chimeric antigen receptor (CAR)-T cell therapy against tumors, widespread application is limited by lengthy and labor-intensive ex vivo manufacturing procedures that result in: (i) very high costs of therapy of up to half of a million dollars; (ii) delays of weeks or months to infuse CAR-T cells to patients with rapidly progressing disease; and (iii) heterogeneous composition and terminal differentiation of infused CAR-T cells as a result of ex vivo culture that limit CAR-T cell engraftment and persistence. Despite significant achievements in this space, reducing the time, costs and regulatory burden remains a deep unmet need in CAR-T cell therapy and significant reducing or eliminating ex vivo procedures remains a critical unmet need. The research outlined in this proposal develops new biomaterials approaches to reduce the time and effort to produce CAR-T cells in vitro, to enhance CAR-T cell phenotype and function. We propose that a short (~hour) pre-activation step with anti-CD3/CD28 antibodies can be immediately followed by transduction and delivery using a biomaterial scaffold. This diversity supplement will support Dr. Trey Davis and allow him to participate in new experiments to extend the scope of Aim 1 studies and will allow him to receive robust training in associated techniques, professional development, and career planning. We expect that our results will provide a basis for a general cellular therapeutic strategy and promote widespread patient access, especially to populations that have been the victims of health disparities.