While complete surgical resection of primary cancer is often possible, the pharmacological treatment of metastasizing cancer is much less successful, mainly because damage to normal tissues limits the amount of cytotoxic drugs that can be safely administered to patients. The efficacy of most of these anti-cancer drugs can, however, be improved substantially if the amount of active drug in the tumor and its distant metastases can be selectively increased compared to the normal tissues. This proposal describes a novel strategy for achieving this goal. We have recently demonstrated that certain subsets of in vitro IL-2 activated lymphocytes, after their infusion into tumor-bearing animals, are remarkably talented in finding and selectively infiltrating malignant tissues. In this proposal we will take advantage of this ability by using tumor-seeking lymphocytes (TSLs) of T cell (CD8+) origin as """"""""guided missiles"""""""" for targeted delivery of prodrug-activators selectively into cancer metastases. The prodrug-activator, attached to the TSLs, can convert systemically administered, non-toxic prodrug into active drug selectively in the metastases. Since very few activated lymphocytes distribute into normal tissues, limited amounts of active drug will be generated in vital organs such as bone marrow and gut. The use of TSLs instead of tumor specific antibodies as carriers of prodrug-activators, an approach known as ADEPT, offers several advantages: expression of tumor specific antigens and production of high amounts of specific antibodies are not needed, and the active migration of the TSLs can ensure a deeper penetration of even hypovascularized tumors compared to passive diffusion of antibodies. In this proposal, we suggest to provide TSLs with prodrug-activating enzymes by different methods and to analyze the tumor-homing capability of the enzyme-carrying TSLs as well as the fate of non-tumor-associated enzymes. Using one of these methods, we have now shown that TSLs are capable of bringing enzyme selectively into tumors and that significant amounts of the enzyme can persist in the tumor tissue for at least 60 hours. These findings strongly supports the feasibility of this strategy. Syngeneic tumor models will be used to test the hypothesis that activation of prodrugs selectively in tumor tissue by enzymes transported to the tumors by TSLs will lead to a better tumor reduction and fewer (if any) toxic side effects than treatment with the maximally tolerated dose of the active drug.
