The main objective of this proposal is to develop a novel cancer vaccine, ApoVax-SVN(tm) based on the use of a proprietary costimulatory chimeric ligand, 4-1BBL, designed to specifically deliver survivin, a tumor associated antigen (TAA) to professional antigen-presenting cells (APCs) and activate them for the generation of an effective anti-tumor immune response with therapeutic efficacy for cancer immunotherapy. Therapeutic vaccines represent an attractive treatment modality for the management of cancer, primarily due to their specificity and ability to induce long lasting immunological memory that may prevent against recurrences. However, their therapeutic potential remains to be realized partially due to the complex nature of interactions taking place between the immune system and cancer cells in the course of tumor progression. These interactions are primarily regulated by two opposing forces; immune mechanisms that target the tumor for destruction and tumor-mediated counter-mechanisms that enable the tumor to evade the immune system. As such, to be effective tumor vaccines must be capable of generating a potent anti-tumor immune response as well as overcoming immune evasive mechanisms for a therapeutic effect. Various cancer vaccine approaches based on the use of TAAs have been developed and shown effective in preclinical models. However, the therapeutic efficacy of these vaccines has been limited in clinical trial settings. Although the reasons for their clinical inefficacy remain unknown, the lack of a strong adjuvant effect, ineffective delivery of TAAs to professional APCs, and/or the presence of significant immunoinhibitory immune evasion mechanisms may contribute to this effect. To overcome some of these difficulties, a novel technology designated as ProtEx(tm) has recently been developed by the Principle Investigator of this application. ProtEx(tm) involves the generation of chimeric immunological ligands with a modified form of core streptavidin, modification of the cell membrane with biotin, and decoration with chimeric proteins. There are three distinct advantages to this technology. First, chimeric ligands exist as tetramers and higher structures, and as such effectively crosslink their receptors on immune cells for potent signal transduction. Second, chimeric proteins can be displayed singly or in a combination on the surface of any biotinylated cell at desired levels in a rapid (< 2 hrs), efficient (100% of the targeted cells), and durable (t1/2= days to weeks) manner without compromising the function of the protein or the cell. Third, chimeric proteins can be conjugated to biotinylated molecules of interest via streptavidin/biotin interaction and used as vehicles to deliver such molecules to cells of interest expressing receptors for the chimeric proteins. The Principle Investigator of this application recently developed a novel, proprietary potential cancer vaccine approach based on the use of 4-1BBL chimeric molecule conjugated to biotinylated TAA antigens. In preliminary studies, this novel vaccine showed potent stimulatory activity on the innate as well as adaptive arms of the immune system and inhibitory activity on T regulatory cells implicated in tumor growth. More importantly, since the last submission of this grant we have demonstrated that immunization with SA-4-1BBL plus a synthetic peptide representing the CD8+ T cell epitope of E7 was effective in eradicating established tumors in a cervical cancer animal model. Therefore, the objectives of this proposal are to test and determine in vivo conditions required for protective as well as therapeutic effects of ApoVax-SVN(tm) vaccine using a B cell lymphoma transplantable model expressing survivin as a TAA. Proof-of-principle confirmation in experimental cancer models will pave the way for testing this novel concept in human clinical trials. Immune system-based treatment of cancer represents an alternative therapeutic approach to classic chemotherapy and radiation treatment, and promises to yield a more definitive solution based on a true molecular approach to cancer. ApoImmune's novel immune system-based therapy, ApoVax104 vaccine, is a new, innovative approach to treating cancer and malignant neoplastic diseases
