Abstract Neoantigens (NeoAg) offer a unique and powerful opportunity for directing a patient’s immune response specifically to cancer cells while avoiding damage to normal tissues. Methods for their reliable identification in tumors of moderate mutational burden such as head and neck squamous cell carcinoma (HNSCC) are lacking, however, as are preclinical experimental platforms for utilizing human material to understand the possibilities and impediments in enabling NeoAg-specific T cells to eradicate established tumors. Working with a focused and collaborative team with expertise in cellular and molecular immunology, bioinformatics, and translational oncology, we have developed a set of novel tools and approaches to address the complex tumor/immune ecosystem in new and incisive ways. These include a unique new model of tobacco-induced HNSCC carcinogenesis which recapitulates many key features of the human disease including gene expression patterns of activated oncogenes, a powerful new combined bioinformatic and functional analysis platform the identification of NeoAg by these tumors can be recognized by the host immune system, a novel preclinical model of combination radio-immunotherapy through which NeoAg-specific responses can be induced and sustained (Sharabi/Sharma), and finally, a new preclinical model of tumor-induced unresponsiveness in the setting of adoptive cellular therapy using human HNSCC patient-derived xenograft (PDX) tumors and patient-matched tumor-infiltrating lymphocytes (TIL) specific for an identified NeoAg. Together, these studies will address the hypothesis that autologous NeoAg-specific T cells can eradicate HNSCC tumors as well as defining the key quantitative and qualitative parameters governing therapeutic efficacy.