Abstract 38: Development of a DC-targeted microvesicle vaccine to intercept the progression of oral preneoplasia to cancer

Abstract

Abstract Background: HPV negative oral squamous cell carcinoma (OSCC) is diagnosed in more than 300,000 people each year worldwide and more than half of these will die within five years despite standard treatment. These cancers are often preceded by the appearance of a preneoplastic lesion, which offers a unique opportunity to identify patients at high risk of developing OSCC and offer them a vaccine that may prevent development of this non-viral cancer. Cancer cell line-derived proteasome-blocked autophagosomes are DC-targeted microvesicles containing tumor-derived short-lived proteins (SLiPs) and defective ribosomal products (DRiPs). SLiPs and DRiPs are short-lived because they are targeted to and degraded by the proteasome, explaining why they are thought to make up the dominant epitopes presented on the surface of cancer cells. This may explain their ability to induce broad anticancer immunity in preclinical models and in patients receiving the vaccine. The human vaccine studied here, DPV-001, was derived from two cancer cell lines. Characterization of the vaccine by mass spectroscopy identified that the vaccine contains more than 100 antigens whose genes are over-expressed by most cancers. Many of these antigens have single amino acid variants that may serve as immunogenic mimetopes, or altered peptide ligands. Further, DPV-001 contains at least 13 antigens from the NCI priority list and multiple toll-like receptor (TLR) agonists packaged into stable double membrane microvesicles that are targeted to CLEC9A+ antigen presenting cells (APCs). We recently reported that every patient receiving vaccine in an NCI-supported phase I/II trial developed or augmented immunity against a large number of putative cancer antigens. Methods: Recently, gene sets developed from a preclinical 4-NQ0 mouse model of oral cancer were shown to enrich for patients with oral preneoplasia that progressed to squamous cell carcinoma (p=0.0495, Foy J-P, 2016). The progressive gene set (PGS) contained 162 genes and we compared this list to results of mass spectroscopy analysis of the DPV-001 vaccine. Results: 94 of the 162 genes contained in the PGS, which enriched for patients with poor oral cancer-free survival, were identified in the DPV-001 vaccine. Conclusions: DPV-001 contains more than 90 proteins for genes (PGS) whose over-expression is associated with progression of oral preneoplasia to OSCC. Based on significant preclinical data documenting induction of protective or therapeutic immunity in animals receiving a DRibble vaccine, coupled with safety data from a phase I/II clinical trial, and evidence that vaccination induces broad immunity against putative cancer antigens in every patient studied to date, we are proposing a pilot clinical trial of DPV-001 in patients with severe oral dysplasia. Citation Format: R. Bryan Bell, Rom Leidner, Carlo B. Bifulco, Christopher Dubay, Tarsem Moudgil, Sam Bookhardt, Glenna McDonnell, Christopher Paustian, Hong-Ming Hu, Walter J. Urba, Traci L. Hilton, Bernard Fox. Development of a DC-targeted microvesicle vaccine to intercept the progression of oral preneoplasia to cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 38.