Structural Immunotherapy: Spherical Nucleic Acid (SNA) Immunotherapy for HPV-Associated Head and Neck Cancer

Squamous cell cancer of the head and neck (SCCHN), ranked 6th in global cancer mortality, is witnessing a transformative shift in its causation due to the escalating prevalence of human papillomavirus (HPV). Current HPV-SCCHN treatment options include surgery, chemotherapy, and radiation. Immunotherapy for HPV-SCCHN has so far been limited to commercially available immune checkpoint inhibitors targeting PD-1 or PDL-1 as a synergistic treatment to chemotherapy. However, even with these options, on average 50% of patients with SCCHN will experience a recurrence/metastasis which has a poor prognosis and a median overall survival <1 year. Therefore, there is a critical need for the development of new and improved treatment options for HPV-SCCHN. To that end, HPV oncoproteins E6 and E7 have emerged as promising targets for vaccine-based therapies. Here we employ chemically tunable spherical nucleic acid (SNA) nanostructures, consisting of a nanoparticle core densely functionalized with DNA, that incorporate selected HPV-SCCHN-specific antigens in a controlled orientation. Indeed, the three-dimensional presentation and overall structural design of SNAs enables effective entry into cells and perturbations to structural and compositional parameters can be altered to achieve a desired therapeutic outcome. Thus, SNAs for immunotherapy allows one to explore the implications of structural presentation of vaccine components in generating epitope-specific T cells. In this study, SNA-based therapeutic cancer vaccines are designed to efficiently deliver adjuvants and tumor-specific antigens, thus activating both innate and adaptive immune systems. We evaluated multiple HPV-16 antigens, with the goal of maximizing immune responses in tumor-burdened humanized murine models and patient-derived tumor spheroid samples. To identify the most potent antigen-SNA formulation, generation of antigen-specific CD8+ T-cells, cytokine production, and HPV cancer-specific cell killing are evaluated. Overall, this work highlights how the structure of SNAs is critical to designing effective therapeutics while providing insights into the molecular interactions between the immune system and cancer cells.