Eliciting Hyperacute Rejection as a Tumor Killing Strategy
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ELICITING HYPERACUTE REJECTION AS A TUMOR KILLING STRATEGY Herpes Amplicon Vector Transfer of the Galactosyltransferase Gene
Charles J. Link*, Daniel J. Hellrung, Tatiana Seregina, and Suming Wang Human Gene Therapy Research Institute 1415 Woodland Avenue, Suite 218 Des Moines, Iowa 50309
INTRODUCTION In 1997 an estimated 560,000 people died from cancer despite all currently available therapies (Parker et al., 1997). New approaches are greatly needed to combat this deadly disease. Gene therapy is among the current experimental strategies for patients with cancer who have failed standard therapy. Despite more than 100 gene therapy trials evidence of success is very limited (Roth et al., 1997). Therefore, new candidate genes and delivery methods must be pursued. Great interest has developed in the idea of using farm animals as a source of organs or tissues for humans. Unfortunately, strong immunological barriers to xenotransplants can destroy a transplanted solid organ within minutes, a process termed hyperacute rejection. The hyperacute rejection model of xenograft survival is typically a vascularized xenograft directly exposed to blood serum (Pruitt, 1994). Research has demonstrated that hyperacute rejection with porcine xenografts transplanted to baboons occurs secondary to porcine gene expression and presentation (Pruitt et al., 1994), (Platt et al., 1990). The enzyme is expressed in all mammalian species including Mus musculus, but not in Old World primates, apes, or humans (Galili et al., 1988). The gene is not active in humans due to the presence of two base pair frameshift mutations (Larsen et al., 1990). catalyzes the transfer of galactose from uridine diphosphate galactose (UDP-Gal) to the N-acetyl-lactosamine acceptors on carbohydrate side chains in a specific on glycoproteins or glycolipids
* Phone: 515-241-8787, Fax: 515-241-8788 Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic / Plenum Publishers, New York, 2000.
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Ab present in the human serum can recognize this epitope (Galili et al., 1988). In fact, preexisting human Ab against represent almost 1% of total human Ab (Galili, 1993) and are the basis for complement-mediated hyperacute rejection (Sandrin et al., 1993). Murine vector producing cells (VPC) implanted into humans is another type of xenograft. Our laboratory and others have demonstrated that murine retroviral VPC and the viral vectors they produce express and therefore are lysed by Ab and complement within 30min after being exposed to human serum (Welsh et al., 1975), (Rother et al., 1995a), (Link et al., 1997). The effect of this serum inactivation on VPC and retroviruses is due to expression on the cells (Rother et al., 1995a), (Link et al., 1997), (Rother et al., 1995b). We are also conducting a trial of intraperitoneal infusion of murine VPC into women with ovarian cancer. Two patients showed some tumor regression despite minimal transgene transfer suggesting that hyperacute rejection of the murine VPC might inhi
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