Preliminary immune response data from this trial is shown in Table 1. 18 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Table 1: Immunogenicity of TriAd vaccine (ETBX-011 and ETBX-061): Development of MUC-1, CEA and Brachyury specific T cell responses by intracellular cytokine staining. The immunogenicity of the TriAd vaccine (ETBX-011, ETBX-051 and ETBX-061) has been assessed in five patients enrolled in the Phase I study following 1 (n=1), 2 (n=5), and 3 (n=3) cycles of vaccination. Antigen-specific immune responses were assessed with a cytometry-based assay. T cells expressing the type I cytokines IFN-γ, IL-2, TNF-α, and/or the degranulation marker CD107a following stimulation with peptide pools encoding CEA, MUC-1, and Brachyury were measured before and after vaccination, as previously described [21, 22]. Including all time points examined, unpublished studies by the LTIB have found that 5/5 patients (100%) developed T cell responses to at least one of the antigens (MUC-1, CEA, Brachyury) encoded by the vaccine, with both CD4+ and CD8+ T cell responses noted. The demonstrated immunogenicity of the TriAd vaccine in advanced and diverse cancer patients enrolled in the Phase I study supports the use of this vaccine in combination immunotherapy studies in more homogeneous populations. 1.2.10 Sequential arm administration of neoadjuvant M7824, N-803 and TriAd vaccine before surgery for advanced-stage, non-HPV associated HNSCC Cumulatively, these data provide the clinical and scientific rationale for the combination of M7824, N-803 and vaccine treatment in the window of opportunity setting before definitive surgical resection in patients with advanced non-HPV associated HNSCC. Studying immunotherapy in newly diagnosed, treatment naïve patients in the neoadjuvant setting allows pathologic, clinical and immune correlative hypotheses to be explored without reducing chance of cure with definitive standard-of-care treatment. Patients with newly diagnosed, advanced HNSCC generally require four to five weeks of treatment planning before definitive treatment begins, providing a treatment window associated with standard of care [23]. Patients will have the opportunity to benefit from neoadjuvant immunotherapy as they await surgical treatment. Since treatment will occur over 2 weeks during this 4-5week window, the treatment schedule will not delay the planned date of definitive surgery. In the window setting, clinical and scientific hypotheses can also be studied quickly given the short duration of neoadjuvant treatment. The multi-arm design of this study with sequential addition of immune-oncology agents allows for assessment of safety and clinical activity in each arm before enrolling subsequent arms. Our primary outcome measures are both based upon pathologic analysis of surgical resected tissues. The significance of a pathologic CR or clinical-to-pathologic downstaging in HNSCC is unknown. This may be determined from neoadjuvant immunotherapy clinical trials, such as the trial proposed here, that can correlate pCR and clinical-to-pathologic downstaging with 1- and 2- 19 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 year recurrence free survival. Since all forms of adjuvant treatment for HNSCC cause post- treatment morbidity, identifying a neoadjuvant treatment that may eliminate the need for adjuvant chemotherapy or radiotherapy, in some patients, could limit post-treatment morbidity in patients that have surgical resection. Adjuvant therapy is based upon result from the surgical pathology report, with clear criteria that dictate whether adjuvant chemotherapy or radiotherapy are indicated. Clinical-to pathologic downstaging may eliminate the need for one or more adjuvant treatments. Pharmacodynamic data from Nant suggest optimal T cell and NK cell is achieved with 15 mcg/kg dosing every 3 weeks. Therefore, a one-time dose of 15 mcg/kg N-803 on day 1 of treatment will be used in this study. M7824 is given at a flat dose of 1,200 mg intravenously. This is the standard phase II dosing of this agent. TriAd vaccine will be given based on dosing from the phase I study of this vaccine platform. 1.2.11 Rationale Summary Clinical outcomes for non-HPV-associated HNSCC are poor. Generating tumor associated antigen-specific T cells (e.g. CEA, MUC1, and brachyury) and then enabling their activity with combination immuno-oncologic (I/O) agents (e.g. M7824 and N-803) has been validated preclinically as a strategy for increasing immune- mediated anti-tumor activity M7824 and N-803 also work in concert to enhance anti-tumor activity in a non-antigen specific fashion (i.e. enhanced NK cell-mediated antibody dependent cellular cytotoxicity). The window between diagnosis and resection of non-HPV associated HNSCC tumors presents a “window” opportunity to test minimally toxic combination immuno-oncologic agents’ ability to improve clinical outcomes. Patients have the opportunity to benefit from immunotherapy during this period of time when they are normally scheduling and awaiting definitive surgery treatment for their HNSCC. Pre-treatment biopsies and post-treatment biopsies or resected tumor samples can provide ample tissue for studies aimed at interrogating the effects of combination immuno- oncologic treatments on tumor microenvironment and correlating those effects with clinical activity. 20 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT 2.1 ELIGIBILITY CRITERIA 2.1.1 Inclusion Criteria  Patients must have histologically or cytologically confirmed, previously untreated intermediate/high risk, p16-negative (if oropharyngeal primary tumor), squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV).  Male or female; Age >18 years.