The overall goal of this research program is to develop new immunotherapies for the treatment of cancer that are based upon the engineered expression of specific immunostimulatory gene products in tumor cells or antigen presenting cells (APCs). Retroviral mediated gene transfer will be used in order to facilitate the screening of a very large number of different gene products for their ability to stimulate systemic antitumor immunity. A variety of different murine tumor models will be employed in order to assess the generality of anti-tumor responses stimulated by transduced cells and to understand any specific characteristics of tumor models which might account for the identification of specific gene products. Particular emphasis will be placed upon the use of spontaneously arising tumors which possess little or no detectable immunogenicity and tumors which do not express class I and/or class II MHC molecules. Studies involving genetically modified APCs will focus upon determination of the optimal cell type and gene product(s) for stimulating antitumor immunity, and definition of the immunological characteristics of antitumor responses directed towards several well characterized murine and human 'tumor antigens' or specific peptides derived from those gene products. Using standard tumor challenge assays and assays involving pre-existing tumor, the applicant will define the immunological characteristics of antitumor responses stimulated by tumor cells or APCs expressing different gene products, quantitate the potency of the responses, and compare the responses obtained with transduced cells to those stimulated by other more classical strategies for immunotherapy involving non-transduced cells (e.g., adoptive T cell transfer and non-specific stimulation of antitumor immunity using agents such as BCG and C. Parvum). Once candidate gene products and vaccine cells are identified, the applicant will investigate new strategies for delivering gene products to the site of vaccination. The applicant will also determine whether immune responses induced by vaccination with transduced cells can be enhanced by the systemic administration of specific cytokines or inhibitors of angiogenesis, and whether specific vaccination schemes can enhance the generation of tumor-specific lymphocytes useful for adoptive T cell therapy.
| Lieschke, G J; Rao, P K; Gately, M K et al. (1997) Bioactive murine and human interleukin-12 fusion proteins which retain antitumor activity in vivo. Nat Biotechnol 15:35-40 |
| Bueler, H; Mulligan, R C (1996) Induction of antigen-specific tumor immunity by genetic and cellular vaccines against MAGE: enhanced tumor protection by coexpression of granulocyte-macrophage colony-stimulating factor and B7-1. Mol Med 2:545-55 |
