Abstract 4577: ONM-500: A STING-activating therapeutic nanovaccine platform for cancer immunotherapy

Abstract

Abstract Background: The efficacy of cancer vaccines requires induction of cancer-specific cytotoxic T-lymphocytes (CTL) to effectively clear established tumors. Orchestration of antigen presentation, co-stimulatory signaling, and innate cytokine signals are necessary steps for tumor-specific T cell activation. The ONM-500 nanovaccine platform utilizes a novel pH-sensitive polymer that forms an antigen-encapsulating nanoparticle and functions both as a carrier for antigen delivery to dendritic cells and as an adjuvant, activating the stimulator of interferon genes (STING) pathway and generating a CD8+ CTL response. Peptide antigens have translational challenges due to limited stability, HLA-type-specific antigen sequence recognition and presentation. Full-length protein antigens alleviate HLA subtype limitation, allowing coverage of multi-immunogenic T cell epitopes in patients. Using the ONM-500 platform with the full-length recombinant E6/E7 oncoproteins from human papillomavirus (HPV) cancers, we have demonstrated great antitumor efficacy in an HPV positive cancer model in animals. Methods: Based on the previously demonstrated STING-dependent T cell activation by ONM-500, the nanovaccine was formulated with full-length HPV16 E6/E7 proteins, and the nanoparticle properties and antigen loading were characterized. In vivo lymph node accumulation following subcutaneous administration was evaluated using fluorophore-labeled ONM-500. Direct binding of ONM-500 polymer to human STING was evaluated using a pull-down assay. Antitumor efficacy of ONM-500 nanovaccine with full length E6/E7 was evaluated using a TC-1 model which overexpresses HPV16 E6/E7 and compared with ONM-500 formulated with peptide antigen. Long-term anti-tumor memory was evaluated in a rechallenge study after 60 days in tumor-free animals. Results: Characterization of ONM-500 nanovaccine shows reproducible particle chemical and physical properties and antigen loading. The nanoparticle size substantiates the effective lymph node accumulation for antigen cross-presentation in dendritic cells following subcutaneous administration. The pull-down assay showed effective binding of the ONM-500 polymer to STING. In TC-1 tumors, ONM-500 nanovaccine containing full-length E6/E7 protein showed 100% overall survival at 55 days. Tumor growth inhibition was also improved over peptide antigen formulated ONM-500. A rechallenge study demonstrated long-term antigen-specific anti-tumor memory response. Conclusions: ONM-500 STING-activating nanovaccines effectively deliver antigens in vivo to lymph nodes to elicit an antigen-specific CTL response. The anti-tumor efficacy in the animal tumor model demonstrates the potential of ONM-500 as a general STING-activating cancer vaccine platform, and full-length E6/E7 incorporated ONM-500 is being developed for HPV-associated cancers. Citation Format: Jason Miller, Min Luo, Hua Wang, Zhaohui Wang, Xinliang Ding, Ashley Campbell, Jonathan Almazan, Stephen Gutowski, Zhijian Chen, Jinming Gao, Tian Zhao. ONM-500: A STING-activating therapeutic nanovaccine platform for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4577.