TRANSPLANTATION OF URB T CELLS CONTAINING THE HSV-TK SUICIDE GENE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: Gene transfer of donor T cells will allow safe infusion of immune reactive cells in high risk transplanation for Fanconi anemia. The goal of this study is to increase the efficacy and safety of alternate donor (unrelated or mismatched related) hematopoietic cell transplantation (HCT) in patients with Fanconi anemia (FA). Donor T cells will be genetically modified to express the herpes simplex virus thymidine kinase (HSV-tk) gene, which results in increased sensitivity of engineered cells to the drug ganciclovir (GCV), which will allow eradication of transduced T cells in vivo should moderate to severe graft-versus-host disease (GVHD) develop. Using these techniques it is anticipated that the positive effects of T cells in HCT (i.e. enhanced engraftment and immune recovery) will be maintained while providing increased control over potentially life-threatening GVHD. To identify cells that have been successfully transduced with the retrovirus, the human truncated nerve growth factor receptor (NGFR) gene is also included in the retroviral construct, resulting in expression of a human cell surface molecule not otherwise expressed on T cells. The presence of NGFR on the surface of T cells will be used to purify transduced cells from non-transduced cells to ensure that nearly all T cells infused will contain the HSV-tk gene. The primary objective of this phase I study is to determine the feasibility, safety and reproducibility of the transduction protocol. The use of the GCRC in this study will be for collection of study samples, monitoring of infusion of experimental cells and the GCRC Cell Therapy Core for immune monitoring and production of the cellular product.