The broad objectives of the research are to develop a next-generation treatment regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. Transplantation of nonautologous hematopoietic stem cells and lymphocytes provide T cell immunity against leukemia cells via the graft-versus leukemia (GVL) effect However, such therapies are currently challenged by host-versus-graft (HVG) and graft- versus-host (GVH) immune reactions. The goal of this proposal is to develop an engineered gene product called TQR*-TK that when expressed in donor T cells will allow bi-directional, pharmacological control of HVG and GVH reactions. T cells expressing TOR*-TK will be resistant to the immunosuppressant rapamycin and sensitive to ganciclovir. In future clinical application, donor T cells transduced with a functional TOR*-TK would be infused following allogeneic HSCT with a nonmyeloablative preparative regimen. Treatment of patients with rapamycin would suppress HVG reactions without affecting GVH reactions, thereby promoting donor cell engraftment and graft-versus-leukemia activity. If GVH disease (GVHD) were to develop, donor T cells could be eliminated by treatment with ganciclovir.
The specific aims of this proposal are: (1) to construct a bi-functional enzyme, TOR*-TK, that will confer upon T cells resistance to the immunosuppressant rapamycin and sensitivity to ganciclovir, and (2) to evaluate TOR*-TK in primary dog T cells to demonstrate pharmacological control of alloantigen-specific immune responses in vitro.
