M.D., University of California, San Francisco, Medicine, 1990.
S.B., Massachusetts Institute of Technology, Life Sciences, 1986.
- 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.
In utero transplantation may soon be in delivery.. Blood. 124(12):1854-5.. 2014.
Autologous hematopoietic stem cell therapy in severe systemic sclerosis: ready for clinical practice? JAMA : the journal of the American Medical Association. 311(24):2485-7.. 2014.
Autologous Hematopoietic Stem Cell Therapy in Severe Systemic Sclerosis Ready for Clinical Practice? Jama-Journal of the American Medical Association. 311:2485-2487.. 2014.
Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 31(12):1530-8.. 2013.
G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment.. Genes & development. 26(22):2499-511.. 2012.
Pulmonary Administration of Water-soluble Curcumin Complex Reduces ALI Severity.. American journal of respiratory cell and molecular biology.. 2012.
Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies.. JAMA : the journal of the American Medical Association. 306(17):1874-83.. 2011.
Blood-based detection of radiation exposure in humans based on novel phospho-Smc1 ELISA.. Radiation research. 175(3):266-81.. 2011.
Identification of radiation-induced expression changes in nonimmortalized human T cells.. Radiation research. 175(2):172-84.. 2011.
Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog leukocyte antigen-haploidentical bone marrow transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 17(2):214-25.. 2011.
Antagonistic and agonistic anti-canine CD28 monoclonal antibodies: tools for allogeneic transplantation.. Transplantation. 91(8):833-40.. 2011.
Outcome of allogeneic hematopoietic cell transplantation from HLA-identical siblings for severe aplastic anemia in patients over 40 years of age.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 16(10):1411-8.. 2010.
A novel monoclonal antibody specific for canine CD25 (P4A10): selection and evaluation of canine Tregs.. Veterinary immunology and immunopathology. 135(3-4):257-65.. 2010.
A preclinical model of double- versus single-unit unrelated cord blood transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 16(8):1090-8.. 2010.
Animal models for medical countermeasures to radiation exposure.. Radiation research. 173(4):557-78.. 2010.
Delaying DLA-haploidentical hematopoietic cell transplantation after total body irradiation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 15(10):1244-50.. 2009.
Immunomodulatory effects of mixed hematopoietic chimerism: immune tolerance in canine model of lung transplantation.. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 9(5):1037-47.. 2009.
SCID dogs: similar transplant potential but distinct intra-uterine growth defects and premature replicative senescence compared with SCID mice.. Journal of immunology (Baltimore, Md. : 1950). 183(4):2529-36.. 2009.
Adoptive immunotherapy against allogeneic kidney grafts in dogs with stable hematopoietic trichimerism.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 14(11):1201-8.. 2008.