Friday, May 17, 2024
5/17/2024
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. Effort to overcome these limitations have focused on closed and automatic manufacturing devices to contain the labor needed to manufacture CAR-T cells ex vivo, and allogeneic off-the-shelf CAR-T cells have been proposed to overcome the need of CAR-T cell manufacturing for each single patient. 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. In vivo generation of CAR-T cells would eliminate the need for ex vivo procedures, prevent the terminal differentiation of ex vivo expanded CAR-T cells and ensure the potency and longevity of autologous T cells as compared to allogeneic CAR-T cell products that are extensively manipulated to prevent rejection and graft- versus-host disease 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 efficacy and persistence in vivo and, finally, to eliminate ex vivo manipulation entirely by generating CAR-T cells entirely within the patient. We propose that biomaterial scaffolds displaying anti-CD3/CD28 antibodies and releasing pro-proliferative interleukins will mediate simultaneous activation and viral transduction of T cells without centrifugation (spinoculation) or transduction agents (retronectin, polybrene) and will facilitate ex vivo genetic reprogramming of T cells by reducing the time and expense of activating naive T-cells and transducing them with viral vectors. We next propose that directly implanting scaffolds seeded with peripheral blood mononuclear cells and CAR- encoding viral vectors will promote release of CAR-T cells into circulation, eliminating ex vivo CAR-T isolation and proliferation protocols to promote a less differentiated cell phenotype associated with longer in vivo persistence. Finally, we propose that, through the inclusion of encapsulated T-cell attracting cytokines, implanted biomaterial scaffolds will generate CAR-T cells entirely in situ through recruitment of host T cells to the scaffold, in-scaffold reprogramming of recruited T cells with resident CAR-encoding viral vectors, and release of reprogrammed CAR-T cells. We expect that our results will provide a basis for a general cellular therapeutic strategy and promote widespread patient access. In addition to the obvious applications in blood cancers, this rational materials-based approach for cellular manufacturing will be adopted to program therapeutic lymphocytes in solid tumors and for other diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
