Exploiting immunostimulatory microbial pattern recognition to improve head and neck cancer therapy - PROJECT SUMMARY The prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC), including oral cancer, remains poor. Radiation therapy (RT) is widely used for clinical management; however, recurrence occurs frequently in patients with advanced diseases. While the rich immune infiltrate often seen within these tumors designates them as prime candidates for immunotherapy such as immune checkpoint inhibitors (ICIs), the response rates in patients with recurrent, metastatic disease is low, indicating an unmet clinical need for developing novel approaches to improve outcomes. In this application, we propose to address these challenges using a novel immune PRIME agent (i.e., Flagrp170), in which a unique microbial pattern recognition sequence is built into a superior antigen-delivery platform, to immunologically program the tumor microenvironment to enhance HNSCC responsiveness to standard of care (i.e., RT, ICIs). This first-in-class multi-functional agent possesses distinct features for optimizing and sustaining immune activation (e.g., forcing cancer cells to produce and secrete a foreign molecule carrying tumor antigenic fingerprints, thereby revitalizing the function of antigen- presenting cells) while concurrently reversing tumor-induced immunosuppression. We will investigate a newly engineered human version of this agent therapeutically and mechanistically to support its bench-to-bedside translation. To accomplish our goal, we will evaluate the immunotherapeutic activity of hFlagrp170 administered intratumorally using multiple oral cancer models and investigate its mechanism of action in orchestrating innate and adaptive antitumor immunity. We will study the interplay between cancer cells and the immune system governed by this microbial chimeric molecule and a less studied microbial pattern recognition signaling pathway. To prevent the tumor recurrence that is often associated with advanced HNSCC following RT, we will leverage the unique property of hFlagrp170 to promote the immunogenicity of cancer cell death and transform the immune landscape of irradiated HNSCC to amplify the ‘abscopal’ response of RT. Additionally, we will use hFlagrp170 to potentiate HNSCC susceptibility to ICIs by increasing tumor-reactive T-cell repertoire and provide mechanistic insights into the hFlagrp170-induced T-cell ‘inflamed’ tumor phenotype. Since an RT and ICI combination regimen being tested extensively in the ongoing trials has yet to show clinical benefits, we will evaluate a tripartite anti-HNSCC approach by capitalizing on the superior immune programming activity of hFlagrp170 to achieve a robust and durable antitumor response. The successful completion of this project is anticipated to establish a scientific framework for rapid translation of this immune PRIME agent, which not only will expand the toolbox of Immuno-Oncology, but also can potentially revolutionize the current treatments of advanced HNSCC.
