Decoy Ligand-Type CAR-T Cells for the Induction of Immune Tolerance
Abstract
Topic Areas: (1) Immunomonitoring of Intestinal Transplants – Development and evaluation of strategies for inducing and maintaining populations of anti- inflammatory regulatory immune cell populations at the transplant site. (2) Tissue Regeneration – Research on novel approaches and therapies to understand mechanisms of immune rejection and obviate the need for chronic toxic immunosuppression in reconstructive transplantation and vascularized composite allotransplantation. Preventing the recipient’s immune system from damaging an organ or tissue transplant remains a significant challenge and is the central problem addressed in this research. Current methods of preventing this damage are associated with toxic side effects and are not effective in preventing chronic rejection or slow deterioration of the graft due to ongoing damage from the immune system. Over 15% of patients receiving an organ transplant develop kidney failure due to chronic toxic immunosuppression intended to prevent loss of the transplanted organ. However, despite immunosuppression, chronic rejection is the leading cause of the failure of a transplanted organ after the first year. This proposal seeks to test the idea that recipient immune cells can be reprogrammed to destroy the cells that would otherwise attack the transplanted organ or tissue. The goal is to create immune tolerance or unresponsiveness of the recipient immune system to the transplanted organ or tissue. Unlike other protocols that rely on general blunting of the immune system or accompanied bone marrow transplants to induce immune tolerance, our approach seeks to use genetically reprogrammed cells to target those immune cells that are responsible for attacking the transplanted organ or tissue. Specifically, this proposal seeks to utilize a new immunotherapy that has been approved for the treatment of leukemia. In leukemia, these cells recognize mutant proteins within the leukemia cells. This leads to the activation of the reprogrammed cells and destruction of the leukemia cells. Much in the same way, we plan to utilize this system to target the very immune cells that would otherwise attack the transplanted organ or tissue if left unchecked. Entirely unique to this approach, the reprogrammed cells would respond strongest to those immune cells that most directly recognize the transplanted organ or tissue. In addition, they would have no effect on cells that do not target the transplanted organ or tissue, resulting normal immune function and absence of global immunosuppression. This research would open a new avenue of investigation for the creation of new and less toxic immune tolerance protocols. It would be applicable in all settings where patients currently undergo treatment with chronic toxic immunosuppression, including solid organ transplantation, vascular composite tissue transplantation, and some autoimmune disorders. Ultimately, this approach may lead to the ability to transplant organs and tissue without the need for chronic immunosuppression or the worry of rejection.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910067
Entities
People
- Ashesh Shah
Organizations
- Thomas Jefferson University
- United States Army