New Engineering Strategy for Harnessing Immune System against Head and Neck Cancer

Project Summary Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive disease with poor overall survival. Despite the success of immune checkpoint blockade (ICB), current forms of immunotherapy benefit less than 15% of HNSCC patients. Therefore, there exists a critical need for new strategies for achieving powerful and durable immune responses with minimal toxicity. Our objective in this application is to design and develop new technological tools for inducing and potentiating T-cell responses against HPV+ HNSCC. To this end, we have engineered a nanoparticle vaccine delivery vehicle that can efficiently deliver antigens and adjuvant molecules to antigen-presenting cells and achieve strong T-cell responses with robust cytotoxic potential. In addition, we have identified a novel strategy for harnessing the immune system by altering the gut microbiome to further amplify nanovaccine-primed T-cell responses. Here, we seek to conduct structure-function studies to understand how these biomaterials interface with our immune system and apply the knowledge gained from these basic studies to potentiate T-cell responses against HPV+ HNSCC. In particular, we will address the following questions by applying the principles of drug delivery, bioengineering, and vaccinology. Can we utilize our strategy to promote antigen and adjuvant delivery to antigen-presenting cells, and improve systemic and local T-cell responses in vivo? Can we employ our vaccine delivery technology to unleash the full cytotoxic potential of T- cells and reverse immunosuppression within HNSCC? Can we alter the gut microbiome to boost efficacy of combination immunotherapy? Can we demonstrate their efficacy in orthotopic models of HPV+ HNSCC, including genetically engineered mouse model of HNSCC? These studies may lead to a novel strategy for harnessing our immune system as the potential treatment of HPV+ HNSCC. The proposal is fully responsive to PAR-19-172 as it will: (1) drive the maturation of an innovative technology for precise immune modulation, (2) create technologies for versatile adjuvant delivery, and (3) enhance the immunotherapeutics for an NIDCR priority disease.