Grants - Designated Grants - California - 2021

Silvio J. Gutkind, PhD

Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need

Cancer immunotherapies have led to major treatment breakthroughs for a number of different cancers, but the majority of head and neck cancer patients do not respond to immunotherapies, and clinical responses are often not durable.  Excitingly, we have demonstrated that targeting aberrant signaling networks in head and neck cancers can also influence anti-cancer immunity, supporting the development of novel, precision immune oncology therapies that significantly improve response profiles. The research outlined in this proposal will combine treatment with a targeted precision therapy – a highly selective anti-HER3 antibody – possessing both direct tumor and immune microenvironment activity, with PD-1 inhibitor immunotherapy. Leveraging our tobacco-signature oral cavity squamous cell carcinoma mouse model, we have obtained strong preliminary results supporting that our therapeutic combination – anti-HER3 + anti-PD-1 – 1) abolishes cancer-driving signaling pathways, 2) reverses the immunosuppressive microenvironment, and 3) potentiates existing antitumor immunity to achieve durable response. In order to develop more effective multimodal immune-oncology therapies that achieve durable response, we propose to employ several innovative techniques with single-cell level resolution to study the tumor-intrinsic effects of targeted HER3 blockade and how these changes ultimately invigorate and synergize with immunotherapies. Our novel approach represents a paradigm-shift in the design of cancer therapies – one in which therapies are rationally selected to target not only specific oncogenic pathways but also to activate cancer immunosurveillance. The proposed studies will provide the first signal-transduction based multimodal precision immunotherapy for head and neck cancer.