DEVELOPMENT OF A LARGE ANIMAL TUMOR MODEL FOR ASSESSING GVL IMMUNOTHERAPY

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DESCRIPTION (provided by applicant): Raimon Duran-Struuck, D.V.M. after completion of his combined laboratory animal residency and T-32 NIH fellowship in comparative medicine [7/21/2007], will join the Transplantation Biology Research Center (TBRC) at MGH as a post-doctoral fellow. This unique research environment provides mentorship by experts in the fields of hematopoietic cell transplantation (HCT) and immunology. His experience and career goals make him an ideal candidate for the SERCA-NCRR/K01 and this award is instrumental for his development into a productive independent investigator. Dr. Duran will be mentored by David Sachs, M.D., and co-mentored by Christene Huang, Ph.D. Non-toxic allogeneic HCT followed by donor leukocyte infusion (DLI) has emerged as the treatment of choice for a variety of lymphohematopoietic malignancies, immunodeficiencies, and marrow failure syndromes. For these diseases, the goal of HCT is the replacement of the recipients' lymphohematopoietic system, with a competent one from the donor. One of the major limitations of this therapy is graft-versus-host disease (GVHD). MGH MHC-inbred miniature swine provide a relevant pre-clinical model for studies of transplantation biology with responses to HCT resembling those of humans. Minimally myelosuppressive preparative regimen leads to stable multi-lineage chimerism following high-dose haplo-identical HCT, without causing GVHD. The lack of transplantable tumors in large animals has limited the study of the graft -versus-tumor (GVT) effects in clinically relevant HCT models. It is our goal in specific aim #1 to develop a swine tumor model for the in vivo assessment of graft-versus-tumor effects of HCT and DLI. Second, preliminary experiments demonstrated that DLI was not effective at increasing donor chimerism in a non-myeloablative swine model. We hypothesize that residual T-cells, and possibly regulatory T-cells, promote chimerism and prevent DLI conversion to donor-type by inactivating donor, recipient and DLI alloreactive T-cells. In Specific aim #2, we will test this hypothesis through the inactivation of regulatory T cells with the goal to improve donor chimerism and enhance the GVL effects in the tumor models (aim #1). The TBRC consists of eight independent laboratories. These include molecular biology, cellular immunology, stem cell biology, study of T cell and antibody diversity and tissue transplantation in small and large animal models. Dr. Duran-Struuck will be exposed to all of these disciplines as his project progresses.