Oncolytic viruses have shown promise as antitumor therapy, but their effects have been limited to local tumors. Tumor vaccines are attractive therapy because tumor cells harbor numerous genetic mutations that could induce specific antitumor immunity. Yet, tumor cells are generally incapable of stimulating an immune response, probably due to inadequate antigen presentation. Heat-shock proteins (HSPs) with the promiscuous ability to chaperone and present a broad repertoire of tumor cell antigens play a critical role in the induction of antitumor immune responses. The goal of this study is to develop a local oncolytic virus therapy that can induce systemic antitumor responses by combining the advantageous features of oncolytic viruses and HSP-based tumor vaccines. We hypothesize that a recombinant oncolytic virus expressing HSP, referred to as """"""""oncolytic HSP vaccine"""""""", can be generated and will possess dual functions: oncolytic activity against local tumor followed by the release of tumor antigens, and potent HSP-mediated antitumor responses against metastatic tumors. In our preliminary study, a recombinant oncolytic adenovirus (Ad) expressing HSP7O was generated and demonstrated to retain oncolytic activity against various tumor cells, and intratumor injection of the oncolytic HSP virus induced systemic antitumor responses.
The specific aims of this proposal are: 1). To test the hypothesis that systemic antitumor immune responses are induced by local therapy with Ad-I{E in murine tumor models capable of supporting human adenovirus infection. 2). To determine whether that enhanced HSP expression by Ad-HE treatment promotes DC tumor infiltration and antigen presentation and which subtypes of tumor infiltrating DCs are critical to induce antitumor immune responses. 3). To test the hypothesis that intratumor immunization with Ad-HE vaccine coexpressing SOCS1-siRNA will overcome tumor-mediated immunosuppression by persistent activation of proinflammatory STAT and NF-?B signaling in infected, SOCS1-silenced tumor-infiltrating DCs and other immune cells. The oncolytic HSP vaccine strategy we propose exploits the advantageous features of oncolytic viruses and HSP-based immunotherapy in a single treatment that may eradicate both local and disseminated tumor cells and may be universally applicable to a broad spectrum of malignant solid tumors.
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