Nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation (HCT) relies on T cell mediated graft-versus-host (GVH) reactions for elimination of the underlying malignant disease. However, disease relapse after allogeneic HCT remains a major complication. Although donor lymphocyte infusion (DLI) is curative treatment for some patients, more effective strategies to enhance the GVH reaction and the graft-versus-tumor (GVT) effect without exacerbating GVH disease (GVHD) are needed to treat patients with more aggressive relapsed or persistent malignancies. We propose to study adoptive immunotherapy strategies experimentally using dogs with stable mixed donor/host hematopoietic chimerism as a model for patients with relapsed or persistent disease after HCT. Stable mixed chimeras generated with the nonmyeloablative regimens outlined in Project 1 will be used. The experimental readout will be conversion of stable mixed donor/host chimerism to all donor chimerism which, we believe, is a powerful in vivo model of GVH and GVT effects, since to treat relapse of malignant hematologic diseases, there should be complete eradication of host hematopoiesis. Two distinct Specific Aims will study clinically applicable strategies to reliably accomplish the conversion without inducing GVHD.
Aim 1 will combine DLI with recipient-derived dendritic cell (DC) vaccination of mixed chimeric dogs. The infused DCs are expected to express minor recipient histocompatibility antigens and costimulatory markers that will prime infused donor T cells which will break immune host-donor tolerance and convert mixed to complete donor chimerism. We will also test if DCs that have been genetically modified to express granulocyte-macrophage colony stimulating factor will enhance this GVH effect.
Aim 2 will involve infusion of donor T cells that have been genetically modified with a lentiviral vector containing a mutant inosine monophosphate dehydrogenase II (IMPDH*) gene so they have become resistant to mycophenolate mofetil (MMF). We anticipate that IMPDH* transduced donor T cells, when infused into stable mixed chimeric dogs treated with MMF, will convert mixed to complete donor chimerism. We hypothesize that MMF will selectively suppress the host immune responses to the IMPDH* transgene while permitting the GVH-effect of IMPDH* transduced donor T cells. If successful in dogs, the results of studies under Aim 1 & 2 will be translated to future clinical trials in Projects 3 & 4 for treating patients with disease relapse after allogeneic HCT.
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