Nearly 2 million people are living with limb loss in the US, with over 185,000 amputations occurring each year. Most of these amputations are sustained by victims of burn injuries, traffic accidents, and medical conditions. Over the past decade, vascularized composite allotransplantation (VCA), the transplantation of limbs and face from a deceased donor, has become a viable alternative for the reconstruction of devastating injuries of these tissues. To date, VCA has rarely been performed on many patients due to the need for intense and lifelong immunosuppression and subsequent toxicity. Tolerance induction protocols may greatly minimize, if not eliminate, the need for lifelong immunosuppression. Clinical application of tolerance protocols could make VCA in many patients as commonplace as liver or kidney transplants. VCA estimates for donor eligibility criteria estimate that approximately 40.3% of deceased donors (from 2008-2015) are eligible to be VCA donors.
While much progress has been achieved, further optimization of the mixed chimerism protocol is urgently needed. Building on our preclinical results, the next iteration towards clinical translation of our studies is to decrease the toxicity of current protocols to extend them for achieving stable mixed chimerism across full MHC-mismatch barriers. Furthermore, most mixed chimerism has only shown to be transient (especially in NHPs and human allograft recipients). The difficulty in achieving durable mixed chimerism and long-term graft acceptance is due to the presence of high levels of alloreactive memory T cells that are known to hinder tolerance induction in both sensitized rodents, and NHPs suggesting that tolerance relies on the peripheral inactivation of donor-specific T cells. Currently, there is no effective and specific strategy for eliminating alloreactive memory T cells. Most existing approaches for eliminating memory T cells administer intense whole-body irradiation with several immunosuppressant combinations that target all the immune cell populations. This shotgun approach results in a severely immune-compromised state in the recipient, which subsequently brings myriads of side effects and complications, including opportunistic infections, reno-vascular dysfunction, and malignancies. As such, a highly specific cell targeting technology is urgently needed to selectively deplete the recipient’s alloreactive memory T cells to achieve stable mixed chimerism.
T cells that are genetically engineered to express chimeric antigen receptor (CAR) produced remarkable results for the treatment of CD19-positive leukemia and lymphoma, leading to complete remissions in pediatric patients and two FDA approved therapies. These results show that immune cells can be selectively targeted and eliminated by CAR T cell technology. A CAR consists of an extracellular antigen-binding domain, a transmembrane domain, the intracellular signaling domain from CD3z and costimulatory domains, such as CD28 or 4-1BB. Recently, to expand the capability of CAR T cells, Dr. Wilson Wong’s lab invented a split, universal, and “programmable” (SUPRA) CAR system that simultaneously encompasses multiple critical features that expand CAR T capabilities. This system can switch targets without reengineering the T cells, finely tune T cell activation strength, and sense and respond to multiple antigens. These features that enable high specificity while targeting multiple antigens make the split CAR T technology uniquely suitable for targeting alloreactive T-cells in recipients and enhancing transplantation tolerance.
The overall goal of our research is to enable a clinically applicable tolerance-inducing regimen for VCA transplantation through the establishment of stable mixed chimerism, augmented by the state-of-the-art adoptive immunotherapy and synthetic biology.