Treatment of pre-established subcutaneous tumor and pulmonary melanoma metastasis with a novel vaccine expressing α(1,3)Galactosyl Xenoepitopes

Abstract

2620 Background: The hyperacute immune response in humans is a potent mechanism of xenograft rejection mediated by complement-fixing natural antibodies recognizing α(1,3)Galactosyl epitopes (αGal) not present on human cells. We exploited this immune mechanism to create a whole cell cancer vaccine to treat melanoma tumors. Methods: Transduction of B16 melanoma cells with a retrovirus carrying the α(1,3)Galactosyltransferase gene (αGT) yielded B16αGal cells. Transduction with a retrovirus carrying the gene for neomycin gave B16NeoR cells. Whole cell vaccines were prepared by γ-irradiation (200 Gy). Results: B16 melanoma vaccine expressing αGal epitopes (B16αGal) effectively treated pre-established subcutaneous and pulmonary B16 tumors in the α(1,3)Galactosyltransferase knockout mouse model, while control B16 melanoma vaccines had no effect. Vaccination with B16αGal induced strong long-lasting cell-mediated anti-tumor immunity extended to αGal-negative B16 melanoma. This was demonstrated by specific in vitro recognition of B16 cells, and successful adoptive transfer of immunity to recipient mice bearing lung melanoma metastasis. Conclusions: This study unequivocally establishes for first time the efficacy of whole cell vaccines expressing αGal epitopes against poorly immunogenic, preestablished melanoma. These data formed the basis for the initiation of this therapeutic strategy in human clinical trial currently underway. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NewLink Genetics NewLink Genetics NewLink Genetics Funded by NewLink Genetics Corporation through a cooperative research and development agreement