Dr. George Georges

- Reducing toxicity of hematopoietic stem cell transplantation: controlling graft-vs.-host disease and studying mechanisms of immune tolerance

The overall goal of Dr. George Georges' research is to decrease the toxicity of allogeneic hematopoietic cell transplantation (HCT), improve control of graft-versus-host disease (GVHD) and study mechanisms of immune tolerance after allogeneic HCT. There are four interrelated areas of investigations; three are laboratory based and one is clinically oriented.

- Pre-Clinical Research

The theme of our pre-clinical research is the use of genetically modified T cells and dendritic cells to enhance engraftment and control GVHD in a model of allogeneic HCT. In addition, we are studying mechanisms of immune tolerance after allogeneic HCT.

1. In the major histocompatibility complex (MHC)-mismatched HCT setting, we are exploring the use of T-cell depleted marrow and the add-back of ex vivo expanded, gene transduced donor T lymphocytes. The T cells are transduced with a “suicide” gene, herpes simplex virus thymidine kinase. When infused at the time of transplant, the transduced T cells enhance engraftment of donor hematopoietic cells. After engraftment is established, the gene modified T cells are ablated with ganciclovir to prevent GVHD. If effective, this will permit HCT for patients without suitable HLA-matched donors.

2. Nonmyeloablative conditioning followed by allogeneic 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 are studying adoptive immunotherapy strategies experimentally in stable mixed donor/host hematopoietic chimeras as a model for patients with relapsed or persistent disease after HCT. The experimental readout is 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. Strategies to break immune tolerance, convert mixed to all-donor chimerism and restore immune tolerance include: (1) dendritic cell vaccines combined with DLI and (2) infusion of donor T cells that have been genetically modified to have an immunologic advantage over recipient cells in order to convert mixed to complete donor chimerism. If successful, the results of these studies will be translated to future clinical trials for treating patients with disease relapse after allogeneic HCT.

3. T regulatory cells and mechanisms of immune tolerance after allogeneic HCT. In the setting of stable mixed hematopoietic chimerism, peripheral tolerance is established with T regulatory cells and tolerogenic dendritic cells. Studies are in progress to isolate and ex vivo expand T regulatory cells and evaluate their in vivo function. We will infuse T regulatory cells into transplant recipients to prevent graft rejection as well as GVHD.

- Clinical Research

We are conducting clinical studies for patients with hematological malignancies with nonmyeloablative conditioning regimens for allogeneic HCT. Disease-specific protocols include acute lymphoblastic leukemia and multiple myeloma. In addition, we are conducting clinical trials of autologous HCT for patients with autoimmune neurologic diseases.