Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection

Background: Some people who get head and neck cancer will need surgery to treat their cancer. Research suggests that immunotherapy drugs may help fight head and neck cancer if given before surgery. In most cases, there is enough time between cancer diagnosis and surgery to test immunotherapy drugs. In this study, researchers are testing the safety and anti-cancer abilities of 3 drugs given before surgery for head and neck cancer. Objective: To learn if giving M7824 alone, or with the TriAd Vaccine (ETBX-011, ETBX-051 \& ETBX-061), or with TriAd vaccine plus Anktiva (N-803) can shrink previously untreated head and neck tumors before surgery or stop the tumors from coming back after all treatment. Eligibility: People age 18 and older who have a head and neck cancer that has not been treated before, and the tumor must be removed with surgery. Design: Participants will be screened in a separate protocol. Participants will have the following tests: * medical history and physical exams * computed tomography or magnetic resonance imaging scans * tumor, mucosa, and skin biopsies * electrocardiograms to monitor heart activity * endoscopies (a tube is inserted through the nose to see the upper airway) * blood and urine tests. All participants will get bintrafusp alfa (M7824) through an intravenous infusion. For this, a small plastic tube is put into an arm vein. Some may also get the TriAd vaccine. It is injected under the skin on the arms or legs. Some may also get N-803. It is injected under the skin on the stomach. Participants will have clinic visits while they are getting treatment and after treatment ends. After treatment ends, participants will have their scheduled surgery. There will be two follow up visits at the National Institutes of Health (NIH) after your surgery. They will be contacted by phone or email every 2 weeks for 3 months. Then they will be contacted every 3 months for 2 years. ...

Background: * Approximately 50% of patients with advanced, non-human papilloma virus (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 programmed cell death protein 1 (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 bintrafusp alfa (M7824) plus Anktiva (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-beta) receptor type 2, a TGF-beta trap. * Adenoviral vaccines targeting known shared tumor antigens can generate antigen-specific T cells. * N-803 is an interleukin 15 (IL-15)/interleukin 15 receptor (IL-15R) alpha super agonist complex that can enhance both natural killer (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 dose limiting toxicities (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 greater than or equal to 18 years * Eastern Cooperative Oncology Office (ECOG) performance status less than or equal to 1 Design: * This protocol is a sequential window of opportunity trial of Anti-PD-L1/TGF-beta trap (M7824) alone and in combination with TriAd Vaccine (ETBX-011, ETBX-051 \& ETBX-061) and N-803 for non-HPV associated resectable Head and Neck Squamous Cell Carcinoma (HNSCC). * Patients will be referred to the National Institutes of Health (NIH) for this immunotherapy treatment from surrounding academic medical centers and private physicians. * Upon referral to the NIH, patients will be rapidly screened, and enrolled on the protocol, if appropriate. * This trial will enroll patients in three arms sequentially to permit safety evaluation before adding the next agent. * In the first arm of 12 patients, M7824 (1200 mg) will be administered intravenously on day 1 and 15. * If no safety concerns, accrual will proceed to the 2nd arm, and 12 patients will enroll with M7824 (1200mg; intravenous) treatment on day 1 and 15 and TriAd vaccine (5 x 10 (11) viral particles (VP; subcutaneous) treatment on day 1 only. * If no safety concerns, accrual will proceed to the 3rd arm, and 12 patients will enroll with M7824 ((1200mg; intravenous) treatment on day 1 and 15 plus TriAd vaccine (5 x 10(11) VP; subcutaneous injection) and N-803 (15mcg/kg, subcutaneously) treatment on day 1. * After obtaining pre-treatment biopsies, imaging and blood collection, patients will receive the neoadjuvant immunotherapy at the NIH Clinical Center. * Patients will then be sent back to their referring providers for their definitive standard of care surgery and adjuvant therapy as indicated based upon pathologic analysis of the surgical specimen. National Cancer Institute (NCI) investigators will have no role in directing the ensuing standard of care surgeries performed at outside institutions. * For consistency in pathologic analysis of resection specimens, tissue blocks and/or slides will be obtained from outside institutions and be reviewed by the NCI Laboratory of Pathology. * It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12 patients apiece, up to 36 evaluable patients may enroll. Accrual is expected to be completed within 2 years.