PROJECT SUMMARY The Wisconsin Head and Neck SPORE is designed to promote translational laboratory and clinical research to improve overall outcome for patients with Head and Neck Cancer (HNC). This highly collaborative research links basic scientists with HNC clinicians to advance novel treatment strategies for this complex cancer population. These patients bear a disproportionate burden from their cancers based on the critical anatomic location of the disease for which treatment can compromise speech, swallow, and breathing function, in addition to creating significant alterations in physical appearance and capacity for social interaction. Efforts to improve cure rates must be carefully balanced with efforts to reduce treatment toxicity to enable enhanced overall quality of life for patients. The broad objectives of this SPORE are to: 1) Promote multidisciplinary translational research in HNC, 2) Improve overall survival and quality of life for patients with HNC, 3) Incorporate new predictive models to test novel HNC treatment strategies, 4) Improve understanding of how immune modulation can augment conventional and experimental treatment responses in HNC, 5) Translate promising new molecules developed at the University of Wisconsin and from Industry through preclinical testing and into HNC clinical trials. The Wisconsin HN SPORE has designed three primary research projects. Project 1 will combine targeted radionuclide therapies (TRT) with immune checkpoint inhibition (ICI) to stimulate enhanced HNC response profiles culminating in a Phase I clinical trial. Project 2 builds a powerful patient-specific bioengineered HNC model system from patient cells that incorporates components of the tumor microenvironment to more accurately predict HNC patient treatment response. The feasibility of using treatment response data from the model to inform postoperative radiation therapy will be tested in a clinical pilot study. Project 3 examines dual targeting of critical receptor tyrosine kinases Axl and MerTK to mediate changes in the immune microenvironment and thereby augment tumor response in HNC patients. The Wisconsin SPORE will support this research with three Cores (Administrative, Pathology and Biostatistics), a Career Enhancement Program and a Developmental Research Program.