In vivo Gene Delivery to Regulatory T Cells to Drastically Reduce the Cost of Regulatory T Cell Therapy

PROJECT SUMMARY Project Title: In vivo Gene Delivery to Regulatory T Cells to Drastically Reduce the Cost of Regulatory T Cell Therapy Organization: GigaMune Inc. PI: David Johnson, Ph.D. Over 9,000 patients will receive liver transplants this year, and about 75% of those patients will survive at least 5 years. Long term immune suppression is required for nearly all patients, but most immune suppressants (e.g., corticosteroids) are systemic rather than targeted. Immune suppressants lead to long-term toxicities such as malignancy (5% incidence), lymphoproliferative disorder (3% incidence), and infections. About 50% of patients never tolerate the transplant to the point where immune suppressants can be removed. Adoptive cell therapies wherein chimeric antigen receptors (CARs) or T cell receptors (TCRs) are engineered into autologous T cells ex vivo have shown strong clinical efficacy and safety. Regulatory T cells engineered with CARs (“CAR Tregs”) are a relatively new concept wherein CARs are used to direct antigen-specific immune suppression. CAR-Tregs are under preclinical and clinical investigation for indications such as transplant and autoimmunity, with the goal of inducing long-term tolerance without toxicities. However, the cost of manufacturing cell therapies is hundreds of thousands of dollars per patient, driving total per-patient costs to up to $1 million per patient. Recent pioneering work used lipid nanoparticles (LNPs) and lentivirus (LVs) to deliver CARs to T cells in vivo, eliminating the need for manufacture of engineered cells ex vivo. GigaMune has developed a novel next- generation lentivirus platform (GigaLentiTM) for in vivo delivery of CARs and TCRs specifically to T cells in vivo. The Specific Aim of this Phase I SBIR project is to use in vitro models to assess the translational potential of chimeric antigen receptor gene delivery to regulatory T cells for liver transplant tolerance, at drastically reduced cost compared to conventional cell therapy.