T cell co-stimulation provided by B7 molecules on the surface of professional antigen presenting cells is essential for allowing antigens to stimulate T cell proliferation and a productive immune response; antigen stimulation in the absence of B7 co-stimulation induces T cell clonal anergy. Elucidation of B7's importance has allowed the design of rational strategies for enhancing the immunogenicity of tumor cells. Murine tumor cells engineered to express B7 ectopically induce an antitumor immune response that can reject established disease. These studies lead one to hypothesize that the immunogenicity of human melanoma antigens may be enhanced to therapeutic benefit by ectopic expression of B7. Whether this strategy will be effective in the therapy of human melanoma cannot be predicted. Many unknown variables, including the inherent antigenicity of human melanoma cells, will influence the outcome, so that efficacy can only be determined by conducting well designed, immunologically monitored clinical trials. Such trials are feasible with the development of an adenovirus vector that can confer ectopic B7 expression on isolated human melanoma cells. The goal of this project is to test in clinical trials whether vaccines of autologous melanoma cells engineered to express the B7 T cell co-stimulatory molecule are safe and therapeutically beneficial. The modified, B7+ tumor cells will be lethally irradiated and reintroduced into the patient by intradermal injection with the intent of stimulating an antitumor T cell response that can destroy unmodified, B7- tumor cells. Furthermore, we will test whether the systemic administration of IL-12 further enhances an immunological response against tumor cells. The reagents and procedures to be utilized will be certified and standardized to generate vaccines of engineered autologous melanoma cells that will be tested in Phase -I clinical trials. In addition, when this strategy is applied clinically, the ability to use cryopreserved melanoma cells will be highly desirable since this may allow cells harvested from patients undergoing a single surgical procedure to be used for repetitive vaccinations.
| Smith, J G; Eck, S L (1999) Molecular characterization of an adenoviral vector resulting from both homologous and nonhomologous recombination. Cancer Gene Ther 6:475-81 |
| Boxhorn, H K; Smith, J G; Chang, Y J et al. (1998) Adenoviral transduction of melanoma cells with B7-1: antitumor immunity and immunosuppressive factors. Cancer Immunol Immunother 46:283-92 |
