Optimizing immunoradiotherapy for HNSCC

Project Summary Head and neck squamous cell carcinoma (HNSCC) is driven by tobacco, ethanol and other carcinogens as well as oncogenic human papilloma virus (HPV). In particular, HPV negative HNSCC has a high rate of mortality and the main curative treatment options for local and regional disease, including surgery, radiation, and

chemotherapy, incur significant morbidity. PD-1 inhibitors are approved for recurrent/metastatic HNSCC yet have low response rates of 14-20%. Furthermore, a recent Phase III trial demonstrated no benefit when a PD-1 inhibitor was combined with chemoradiation using large radiation fields targeting tumor and lymph nodes. While

the tumor immune microenvironment is key to the activity of immunotherapy, the role of draining lymph nodes in the efficacy of immunotherapy is poorly understood and the impact of conventional therapies anti-tumor immunity deserves further investigation. Our preliminary data demonstrate nodal irradiation or surgical removal of draining

lymph nodes completely blocks the anti-tumor activity of PD-1 inhibitors, and surgical disruption of lymphatic channels alone while maintaining intact draining lymph nodes also blocks immunotherapy responses. Mechanistically, we have identified cDC1 and B-cell antigen presenting cells in draining nodes as key immune

effectors coordinating anti-tumor immune responses. Further, a Phase I trial of immunoradiotherapy using PD-1 inhibitors combined with lymphatic sparing stereotactic radiation (SBRT) demonstrates a remarkable 67% complete pathologic response rate in HNSCC patients. Our central hypothesis is that intact, functional

draining lymphatics and lymph nodes are critical for anti-tumor immunity and that lymphatic preserving IRT in HNSCC will maximize anti-tumor responses. To explore this hypothesis, we will use animal models of HPV negative HNSCC to 1) determine the role of the draining sentinel lymph nodes in generating and

coordinating immune responses during immunotherapy and SBRT based immunoradiotherapy in HPV negative HNSCC, and 2) maximize immunotherapy responses in HNSCC by optimizing treatment sequencing, radiation targeting, and enhancing antigen presentation in draining lymph nodes. To validate this hypothesis in patients,

we will define immune phenotypes that correlate with major pathologic responses from a clinical trial of neoadjuvant immunoradiotherapy in HPV negative HNSCC patients. Completion of this project will elucidate the role of draining sentinel lymph nodes in coordinating anti-tumor immune responses, identify optimized

sequencing and novel combinatorial immune therapies in HNSCC, and define immune signatures in patients with complete responses to immunoradiotherapy in HSNCC. These insights will guide and improve the design of therapeutic strategies that leverage draining lymph nodes in coordinating anti-tumor immune response and

improve outcomes in HNSCC and other solid tumor patients.