Background Efficacy of cancer vaccines requires the induction of tumor antigen-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 platform1-2 utilizes a novel pH-sensitive polymer that forms an antigen-encapsulating nanoparticle and functions both as a carrier for antigen delivery of both peptide and protein antigens to dendritic cells and acts as an adjuvant, activating the stimulator on interferon genes (STING) pathway and generating a CD8+ CTL response. Peptide antigens have translational challenges due to complex formulations and/or HLA-type-specific antigen sequence recognition, processing and presentation. Full-length protein antigens alleviate HLA subtype limitation, allowing coverage of multi-immunogenic T cell epitopes in patients. Pairing ONM-500 adjuvant with the full-length E6 and E7 oncoproteins from human papillomavirus (HPV) cancers shows great potential to treat HPV-associated cancer in patients.
Methods Based on the previously demonstrated STING-dependent T cell activation by ONM-500 , the nanovaccine was formulated with full-length HPV16 E6 and E7 proteins (recombinant), and the nanoparticle properties and antigen loading were characterized. In vivo lymph node accumulation following subcutaneous administration was evaluated using fluorescent nanovaccines. Direct binding of ONM-500 to recombinant human STING (CTD) was evaluated using isothermal titration calorimetry (ITC) compared to the endogenous ligand 2’,3’-cGAMP. Antitumor efficacy was evaluated in multiple syngeneic tumor models, including the TC-1 model which overexpresses HPV16 E6 and E7 with the ONM-500 vaccine in combination with anti-PD-1 checkpoint inhibitor. Long-term anti-tumor memory was evaluated in a follow-up rechallenge study after 60 days in tumor-free animals.
Results Characterization of ONM-500 nanovaccine shows reproducible particle chemi-physical properties and antigen loading. The nanoparticle size substantiates the effective lymph node accumulation for antigen cross-presentation in dendritic cells following subcutaneous administration. ITC studies with human STING demonstrated effective binding by ONM-500 adjuvant. The nanovaccine anti-tumor efficacy was previously demonstrated in melanoma, colorectal, and HPV-associated syngeneic tumor models. In TC-1 tumors, ONM-500 nanovaccine containing full-length E6/E7 protein showed 100% overall survival at 55 days (figure 1). Tumor growth inhibition was also improved over E7 antigen peptide formulated nanovaccine. 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 antigen-specific CTL response. The anti-tumor efficacy in multiple tumor models demonstrates the potential of ONM-500 as a general STING agonist cancer vaccine platform, and full-length E6/E7 incorporated ONM-500 is being developed for HPV-associated cancers.
Ethics Approval All animal procedures were performed with ethical compliance and approval by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center (Protocol No. 2017-101954) and Pennsylvania State College of Medicine (Protocol No. 47682).
Luo M, Wang H, Wang Z, Cai H, Lu Z, Li Y, Du M, Huang G, Wang C, Chen X, Porembka MR, Lea J, Frankel AE, Fu YX, Chen ZJ, Gao J. A STING-activating nanovaccine for cancer immunotherapy. Nat Nanotechnol 2017; 12:648–654.
Luo M, Liu Z, Zhang X, Han C, Samandi LZ, Dong C, Sumer BD, Lea J, Fu YX, Gao J. Synergistic STING activation by PC7A nanovaccine and ionizing radiation improves cancer immunotherapy. J Control Release 2019; 28:154–160.
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