This program grant has its basis in the novel, recently discovered observation that tumor cells will be killed by the drug ganciclovir if they are in contact with or contiguous to other tumor cells which have been genetically modified to contain the herpes simplex virus thymidine kinase gene (HSV-TK). The tumoricidal effect a) is produced in in vitro cell- culture or in vivo in animals with established intraperitoneal tumors, b) is not cell-type or species specific, c) is conferred with live or irradiated gene-modified cells, and d) apparently involves apoptotic cell- death presumably by transfer of vesicles containing GCV from dying gene- modified to unmodified cells. These findings lead to development of an approved Phase I clinical protocol to determine the efficacy of using HSV- TK+ tumor cells for treatment of recurrent intraperitoneal human ovarian carcinoma. The proposed studies will build upon and expand these findings and consist of four research projects and three supporting core facilities. the principal objectives are to develop new methods for cancer therapy which have wide applicability to diverse cancers, using genetically modified tumor cells which produce tumoricidal proteins or which potentiate a host's anti-tumor immune response. the four research projects which are intimately coordinated and interdependent as to purpose should fulfill these goals, and have as principal investigators physician/scientists with established track records in gene-therapy and related fields, and in the evaluation and development of new therapies for treatment of cancers. Project 1 lead by Drs. Camille Abboud and George Abraham is concerned with advancing our knowledge of the apoptotic cytotoxic process in HSV-TK+ cells, and clarifying the role(s) of cytokines in conferring sensitivity or resistance to killing after GCV treatment. Project 2 (Dr. Scott Freeman) will determine whether the cytotoxic effect on tumors produced by administering HSV-TK+ cells and GCV can be enhanced by administering HSV- TK+ cells with immune cytokines either parenterally or as gene-modified cells. Project 3 under Dr. James Zwiebel will take advantage of the angiogenic and vascular properties of growing tumors, and in a murine angiogenic tumor model will develop methods to specifically target gene modified endothelial cells directly to sites of primary tumor cell growth. Project 4 directed by Dr. Craig McCune will be a Phase I gene therapy trial which tests the efficacy of using HSV-TK+ tumor cells for treatment of recurrent ovarian cancer. Based on the results and from the findings in the other projects, similar gene-therapy methods will be adapted for treatment of renal and colon cancers. By careful interdigitation of projects and unification of purpose toward a common goal this program grant should point to new and widely used methods for gene-therapy of cancers.
