Dr. George Georges is strongly committed to a research career as a clinician scientist. His immediate career plans are to continue his research project under the mentorship of Dr. Rainer Storb at the Fred Hutchinson Cancer Research Center (FHCRC) to further develop the experience and skills using the dog model of transplantation to study T-cells and the control of graft versus host disease (GVHD). His long term career goals are to become an independent investigator in transplantation biology and carry out translational studies that will lead to improvements in the treatment of cancer and other diseases with stem cell transplantation. The FHCRC provides an outstanding environment for development of Dr. Georges' research career. The goal of this research project is to develop ex vivo expanded alloreactive cytotoxic T-lymphocytes (CTL) that can safely enhance engraftment of donor hematopoietic stem cells. The hypothesis to be tested is that addback of recipient-specific CTL can enhance engraftment without severe GVHD. The ex vivo transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene into CTL will make T-cells susceptible to elimination with the antiviral drug ganciclovir once engraftment is established but before onset of GVHD. This will be tested in two transplant models. The first is in major histocompatibility complex (MHC) haploidentical mismatched recipients of T-cell depleted stem cells following 920 cGy total body irradiation (TBI). We will ask if donor CTL can prevent graft rejection. After engraftment we will treat GVHD with ganciclovir. If successful, this could translate into universal donor availability for patients requiring hematopoietic stem cell transplantation. The second model is with MHC-matched littermates using a nonmyeloablative regimen. Following 200 cGy TBI before and 5 weeks of immunosuppression with mycophenolate mofetil and cyclosporine after marrow transplant, stable mixed hematopoietic donor-host chimerism is established. We will test if donor CTL specific for host minor histocompatibility antigens can convert mixed to complete donor chimerism. If successful this would make MHC-matched stem cell transplantation less toxic.
