Deciphering the mechanism of response to novel HPV-specific viral immune therapy in HPV associated head and neck cancer

Summary Over the past several decades, there has been a dramatic increase in incidence of human papillomavirus associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), which is now the most common head and neck cancer in the US. As treatment of HPV+ OPSCC with chemoradiotherapy is associated with substantial treatment-related toxicity, the current clinical focus has turned to immunotherapy with antibodies (e.g. nivolumab) targeting PD-1, a T cell inhibitory receptor that functions as immune checkpoint. However, our recently completed clinical trial evaluating the addition of nivolumab to chemotherapy failed to demonstrate a significant improvement over chemotherapy alone, posing an urgent need for new therapeutic strategies for patients with HPV+ OPSCC. As checkpoint inhibitors are non-specific immunotherapies and do not leverage the tumor antigen specificity represented by HPV, further improvement in immunotherapy is contingent upon the development of new immunotherapeutic strategies specifically targeting HPV-positive OPSCC. Generation and maintenance of the HPV+ malignancy requires consistent expression of viral oncoproteins (E6 and E7). Therefore, they represent attractive targets for the development of HPV-specific immune activators. The HB-200 is a novel immunotherapy platform that contains two attenuated, replicating viral vectors based on either lymphocytic choriomeningitis virus (HB-201) or Pichinde virus (HB-202), that express the same non- oncogenic but highly immunogenic HPV E7E6 fusion protein, and infect antigen presenting cells to induce HPV- specific T cell responses. Preliminary data from our in vivo and ongoing clinical studies indicate that HB-200 viral therapy may induce stronger anti-tumor responses than immune checkpoint blockade with chemotherapy, suggesting its significant therapeutic potential for patients with HPV+ OPSCC. However, a subset of patients fail to develop deep responses to viral therapy, and the mechanisms underlying either a robust anti-tumor immune response or resistance remain unknown. In this proposal, we will use primary tumor biopsies and plasma samples collected from patients treated with HB-200, coupled with sophisticated preclinical mouse models and innovative molecular approaches to delineate the immunogenetic mechanisms that dictate patients’ clinical responses to this novel form of immunotherapy. This proposal can provide vital insights and build solid foundation for further optimizing this new form of immunotherapy, and has the potential to result a significant clinical advancement in immunotherapy for patients with not only HPV+ OPSCC, but also unveil a new path for treating other viral-associated malignancies.