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Immunity to the (1,3)Galactosyl Epitope Provides Protection in Mice Challenged with Colon Cancer Cells Expressing (1,3)Galactosyl-transferase

A Novel Suicide Gene for Cancer Gene Therapy¹

Stoddard Cancer Research Institute, Iowa Methodist Medical Center, Des Moines, Iowa 50309, and Department of Immunobiology, Iowa State University, Ames, Iowa 50011

Human immunity to (1,3)Galactosyl epitopes (Gal) may provide the means for a successful cancer gene therapy that uses the immune system to identify and to destroy tumor cells expressing the suicide gene (1,3)Galactosyltransferase (GT). Innate antibody specific for cell surface Gal constitutes a high percentage of circulating IgG and IgM immunoglobulins in humans and is the basis for complement-mediated hyperacute xenograft rejection and antibody-dependent cell-mediated cytotoxicity. In humans, the gene for GT is mutated, and cells do not express the Gal moiety. We hypothesized that human tumor cells induced to express the Gal epitope would be killed by the hosts’ innate immunity. Previous in vitro work by our group has demonstrated complement-mediated lysis of Gal-transduced human tumor cells in culture by human serum. To induce antibodies to Gal in this in vivo study, GT knockout mice were used to determine whether immunization with Gal could provide protection from challenge with Gal-expressing murine MC38 colon cancer cells. Knockout mice were immunized either a single time, or twice, with rabbit RBC. Antibody titers to Gal measured by indirect ELISA were significantly higher in mice immunized twice and approached the titers observed in human serum. Anti-Gal antibodies were predominantly of the IgG1 and IgG3 subtype. Immunized knockout mice were challenged i.p. with varying doses of Gal⁺ MC38 colon carcinoma cells. Nonimmunized control groups consisting of GT knockout mice, and wild-type C57BL/6 mice were challenged as well with MC38 cells. Immunized mice survived and exhibited slower tumor development in comparison to nonimmunized knockout and control mice. This study demonstrates, in vivo, the protective benefit of an immune response to the Gal epitope. Our results provide a basis to pursue additional development of this cancer gene therapy strategy.

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