A novel suicide gene for therapy of graft versus host disease. The use of small molecules to control the expression and/or activity of transgene products is an attractive strategy for initiating signaling pathways that regulate cellular functions including cell death. A novel inducible suicide gene based on the induction of apoptosis through oligimerization of the human Fas protein by a bivalent synthetic drug ligand has been developed and could potentially overcome the problem of immune responses to protein products encoded by suicide genes derived from pathogens. The Fas suicide construct, termed NGFR-2FKBP-Fas is made up of three human proteins expressed as a chimeric molecules. The molecule consists of the extracellular and transmembrane domains of the low affinity nerve growth factor receptor, two copies of the FK506-binding protein., and the cytoplasmic domain of Fas. A bivalent drug AP1903 that will bind to FKBP can be administered to induced oligomerization of the linked Fas receptor and signal apoptosis in the target cell. In the proposed study the strategy of using a synthetic drug to regulate the survival of gene- modified cells in vivo will be evaluated in allogeneic hematopoietic stem cell transplant recipients who receive donor T lymphocytes modified to express NGFR-2FKBP-Fas as adoptive immunotherapy for relapsed chronic myeloid leukemia. In this setting, the transferred T cells may eradicate the leukemia but also cause persistent graft-versus-host disease. The introduction of NGFR-2FKBP-Fast will bring these cells under persistent graft-versus-host disease. The introduction of NGFR-2FKBP- Fas will bring these cells under pharmacologic control and permit their ablation in vivo in patients with GVHD. These studies will provide insight into the clinical use of chemical dimerization agents to regulate transgene function and may identify a suicide gene which is not immunogenic in humans and could be broadly applied to control graft versus host disease.
The specific aims are: 1.) To determine the safety, in vivo persistence, and biologic activity of adoptive immunotherapy with donor T lymphocytes modified by retrovirus mediated gene transfer to express LNGFR-2FKBP-Fas for patients with relapse of CML after allogeneic HCT. 2.) To determine if LNGFR-2FKBP-Fas transduced T lymphocytes can be ablated in patients who develop graft-versus-host disease by the administration of the synthetic FKBP binding drug AP1903. 3.) To determine if a host immune response is elicited to the LNGFR-2FKBP-Fas transgene product.
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