The UWCCC Biotherapy Program has a long interest of integrating clinical biotherapy trials with preclinical and clinical immunological observations, focusing on the role of immunotherapy in the treatment of cancer patients. Our recent approaches have centered around increasing anti-tumor activity by endogenous tumor reactive T cells by delivering BRM genes using a novel particle mediated gene transfer (PMGT) technology. Using this technology, we have demonstrated that we can induce effective antitumor immunity by inserting the cDNA for genes such as IL-12, GM-CSF, or IFN-gamma into tumor cells or peritumor epidermal tissues. Building upon these observations, we propose four years of clinical trials testing the hypothesis that vaccines consisting of BRM-gene transfer, using the PMGT technology, can be safety administered and will result in effective antitumor immunity. Specifically, during these four years, we will perform four clinical trials to: A-1 and A-2: Determine whether gene transfer of GM-CSF cDNA, by PMGT technology, will result in local transgenic production of GM-CSF and a local inflammatory response sufficient to stimulate a systemic antitumor immune response; and to evaluate and compare the safety, toxicities and biological effects of ex vivo PMGT of GM-CSF cDNA to tumor cells, and in vivo PMGT of GM-CSF cDNA to nontransformed tumor vaccination sites (years 1 and 2): B: Examine and compare the effects of ex vivo, or in situ gene transfer of IL-12 cDNA on local transgenic production of IL-12, and the generation of both a local and systemic antitumor immune response (years 2 and 3); C: Determine and compare the safety, toxicity and biological activity of two different dose levels of c-DNA for MART-1 either alone or in combination with two different dose levels of cDNA for B7-1 and or IFN- gamma (years 3 and 4). In close collaboration with Programs II and IV, detailed biological endpoints on each of the clinical trials will be evaluated to determine the effects of gene therapy on local and systemic transgene expression, and to characterize the local and systemic immune response. These trials will result in a deeper understanding of the biological and clinical effects of a novel method of gene delivery for vaccine treatment of patients with cancer.
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