(previously NantCell)ImmunityBio, Inc. (previously NantCell) Commercial Agents: None 2 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 PRÉCIS Background: Approximately 50% of patients with advanced, non-HPV associated head and neck squamous cell carcinoma (HNSCC) will develop locoregional or distant relapse within two years of completing definitive standard-of-care treatment. Two ongoing clinical trials investigating neoadjuvant PD-1 blockade before surgical resection of HNSCC suggest that immunotherapy can both cytoreduce existing disease before surgery and reduce the risk of locoregional or distant disease relapse after surgery. Preliminary data from these studies suggest neoadjuvant treatments can be administered without delaying planned surgical intervention. Experiments conducted by the Laboratory of Tumor Immunology and Biology (LTIB) demonstrated synergistic activity with tumor-targeted adenoviral vaccine plus M7824 plus N-803 in humanized mice bearing human carcinomas and in vitro studies. M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF- β) receptor type 2, a TGF-β trap. Adenoviral vaccines targeting known shared tumor antigens can generate antigen-specific T cells. N-803 is an IL-15/IL-15Rα super agonist complex that can enhance both NK cell and T cell anti-tumor activity via expansion and activation. Activity observed with neoadjuvant anti-PD-1 agents alone provides rationale for testing of M7824 alone and in combination with other immune-oncologic agents that have been shown to work in concert with M7824 in preclinical studies. Analysis of pre- and post-treatment tissues from HNSCC patients presents a unique opportunity to interrogate the effects the above treatment(s) on tumor. A dose escalation of N-803 in combination with a flat dose of M7824 was conducted at the National Cancer Institute. Thirteen patients have been treated with the combination. No DLTs were observed. Objectives: Determine the rate of pathologic complete response (pCR) or clinical-to-pathological downstaging in patients with previously untreated intermediate/high risk, non-HPV associated , squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV) who receive any of the three proposed treatments: M7824 alone, M7824 plus TriAd vaccine, or M7824 plus TriAd vaccine plus N803 prior to definite surgery. Eligibility: Patients must have histologically or cytologically confirmed, previously untreated intermediate/high risk, p16-negative (if oropharyngeal), squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV) Men or Women; Age >18 years ECOG performance status ≤ 1 3 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Design: This protocol is a sequential window of opportunity trial of Anti-PD-L1/TGF-β trap (M7824) alone and in combination with TriAd Vaccine and N-803 for non-HPV associated resectable Head and Neck Squamous Cell Carcinoma (HNSCC). Patients will be referred to the NIH for this immunotherapy treatment from surrounding academic medical centers and private physicians.