Chaperone-based tumor therapy delivered by viral vectors

DESCRIPTION (provided by applicant): The efficacy of molecular chaperones as adjuvants for the induction of anti-tumor immunity has been demonstrated in many laboratories over the last two decades. Similarly, the exploration of the therapeutic use of poxviruses in cancer treatment has a long and diverse history. These findings have led us to hypothesize that poxviruses would be an efficient and effective way to accomplish the intracellular delivery of molecular chaperones into tumor cells where they could sample the peptide epitopes generated within the tumor and, upon lysis of the infected tumor cells, release the chaperones for uptake by the immune system. The chaperones would then provide these tumor-specific peptides to the MHC Class I antigen-presenting molecules for cell-surface expression. In this proposal, our combined expertise in chaperone structure and function and Vaccinia virus (VV) genetics and viral vector gene therapy is extensively integrated with the experience developed by VirRx in murine tumor models. This puts us in an excellent position to test comprehensively the feasibility of using Vaccinia virus vectors capable of expressing high levels of molecular chaperones to induce therapeutically effective tumor immunity. At Saint Louis University, we will accomplish two Specific Aims. We will construct and characterize W vectors carrying an expressible cDNA insert encoding GRP94, an abundant chaperone of the endoplasmic reticulum and we will assess the ability of the expressed GRP94 to induce cytotoxic T cells. At VirRx, we will test the efficacy of the W-GRP94 vectors for the induction of anti-tumor immunity using in vivo murine tumor models.