Because major clinical problems associated with glioblastoma are local expansion, invasion and metastasis, approaches that locally deliver antitumor agents intracranially are becoming an important frontier in the therapy of brain cancer. The applicant?s group has explored the local delivery of cytokines in murine models of brain cancer for activating antitumor immunity. This group has shown that sustained delivery of cytokines can be achieved either through the introduction of irradiated cytokine gene-transduced cells or via incorporation of cytokine protein into degradable biopolymer microspheres. Towards this goal, with cytokine gene-transduced cells, they have explored the paracrine delivery of three cytokines, GM-CSF, IL-2 and IL-12, based on the earlier demonstration of bioactivity of locally delivered cytokine in the periphery. These studies showed that local delivery of IL-2 and IL-12 was quite active in preventing the growth of stereo-tactically implanted brain tumors. There was synergy between intracranial paracrine delivery of IL-2 and locally delivered chemotherapy through the use of biopolymer delivered BCNU. For the current application, the specific aims are: 1) to develop biopolymer delivery systems for cytokines and directly compare the efficacy of biopolymer microspheres with transduced cells as local delivery vehicles for cytokines, 2) to evaluate evidence of synergy between different cytokine combinations using gene transduced bystander cells, particularly IL-2 family (IL-2, IL-15) and IL-12 family (IL-12 and IL-18), 3) to extend the evaluation of synergy between single and combination local cytokine delivery and other polymer-delivered chemotherapy drugs (including doxorubicin, taxol, carboplatin and camptothecin), 4) to evaluate combinations between peripheral vaccination, to activate tumor specific immune responses, and local delivery of cytokines with or without local polymer delivery chemotherapy, and 5) to evaluate tumor specific immune responses using murine models in which immunodominant tumor antigens have been identified.
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