The goal of this project is to develop an innovative biodegradable hydrogel (BH) based cytokine carrier for intra-tumoral immunotherapy of human oral cancer (OC). Despite aggressive multimodality treatment, Ioco-regional recurrence is the principal pattern of treatment failure of oral cancer. We hypothesize that BH can be engineered for local sustained release of pro-inflammatory cytokines into the tumor microenvironment to mobilize tumor associated lymphocytes that will eradicate tumor cells. The potent antitumor effects of cytokines have already been established. However, toxicity associated with systemic administration of cytokine limits its clinical application. Intra-tumoral cytokine administration strategies have been shown to improve efficacy of cytokine treatment and minimize the toxicity. The essential criteria of such local cytokine administration are control of dose, release kinetics and preservation of cytokine bioactivity. Although gene therapy has provided proof of this principle, but has failed to meet all the requisite criteria. In this project a BH-based cytokine-delivery system will be developed as a collaborative project between Biomedical Engineering Program of Cornell University and Head and Neck Oncology Division of NYU Cancer Institute. In addition to its biocompatibility, versatility in formulation and technical simplicity, our preliminary results have demonstrated that BHs can be formulated for loading various proteins, controlling their release kinetics and preservation of cytokine bioactivity. In Aim 1, BH formulations will be engineered to optimize the cytokine release kinetics (amount, duration and pattern) and to confirm preservation of cytokine bioactivity. In Aim 2, this newly developed BH-delivery system will be investigated in a chimeric human/SCID mouse model of OC established in our laboratory. This tumor model allows co-engraftment of human tumor and autologous lymphocytes and proved to be effective for in vivo evaluation of intra-tumoral immunotherapy. The anti-tumor efficacy of BH mediated delivery of IL-12 alone or its synergistic combination will be optimized in this model. A preliminary lymphocyte subset depletion study will also be conducted to provide insight into cellular components responsible for anti-tumor activity with intra-tumoral cytokine treatment. This may serve as a basis for future complete and systematic anti-tumor mechanism study. The results from this study will establish a novel intratumoral immunotherapy for OC, which may be readily translated into clinical trials. This potential therapeutic strategy, hydrogel mediated controlled release of cytokine into tumor microenvironment, may be used in other solid tumors.