Chimeric Antigen Ligand (CAL) T Cell Therapy for the Prevention of Allograft Rejection

There are nearly 2 million people living with limb loss in the US, where over 185,000 amputations occur each year. Over the last decade, our capabilities to conduct reconstructive transplantation, such as vascularized composite allotransplantation (VCA) from diseased donors, has vastly improved to become a viable alternative for some candidates. However, donors and recipients of these transplants are commonly not HLA identical, resulting in an immune response due to interactions between the recipient’s alloreactive T cells that recognize “non-self” antigens and the donor cells that present these mismatched “non-self” MHC-antigen complexes. The most common method of inducing tolerance to the donor organ is by lifelong administration of immunosuppressive drugs that come with the risk of opportunistic infections and toxicities. As such, there is an urgent need for a highly specific cell targeting technology to restore immune tolerance without the need for life-long immunosuppression. Our approach to achieving this is to engineer split Chimeric Antigen Ligand (CAL) T cells that use TCR-targeting adapter molecules to specifically deplete the recipient’s immune cells that are reactive against the donor, while preserving other T cell subsets to maintain a robust immune system. This system has the ability to switch targets without reengineering the T cells and respond to multiple antigens to target only alloreactive T-cells and enhance transplantation tolerance. This approach provides a flexible therapeutic platform that can be adapted beyond transplantation to a range of autoimmune diseases including type 1 diabetes, rheumatoid arthritis, vitiligo and other disorders that originate from autoreactive T cell dysfunction.