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

* 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 greater than or equal to 18 years.
* Eastern Cooperative Oncology Group (ECOG performance status less than or equal to 1.
* Prothrombin time (PT) and partial thromboplastin time (PTT) within normal institutional limits. Patients with prolonged PTT determined to be due to lupus anticoagulant will not be excluded.
* Patients must have adequate organ and marrow function as defined below:

  * Absolute neutrophil count greater than or equal to 1000/mcL
  * Platelets greater than or equal to 100,000/mcL
  * Hemoglobin greater than or equal to 10.0 g/dL
  * Total bilirubin within normal institutional limits; in patients with Gilbert's, less than or equal to 3.0 mg/dL
  * Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than or equal to 3X upper limit of normal.
  * Creatinine within 1.5X upper limit of normal institutional limits
* The effects of M7824, TriAd Vaccines (ETBX-011, ETBX-051 \& ETBX-061), and Anktiva (N-803) on the developing human fetus are unknown. For this reason, men and women of child-bearing capacity must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study and maintain such contraception until 2 months following the last dose of any study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* Ability of subject to understand and the willingness to sign a written informed consent document
* Patients with successfully treated hepatitis C virus (HCV) are eligible if HCV viral load is undetectable.

EXCLUSION CRITERIA:

* Patients who are immunocompromised as follows:

  * Human immunodeficiency virus (HIV) positive patients not on or not compliant with appropriate anti-retroviral therapy, patients with newly diagnosed (i.e., \< 6 months) HIV, patients with an HIV viral load exceeding 400 copies/mL, HIV+ patients with a cluster of differentiation 4 (CD4) count \< 150 cells/L, and HIV+ patients on antiretroviral therapy \< 1 month are excluded. HIV-positive patients will also be excluded if the principal investigator (PI) determines that there is a clinically significant drug-drug interaction.
  * Chronic administration (defined as daily or every other day for continued use \>14 days) of systemic corticosteroids or other immune suppressive drugs, within 14 days before treatment on study. Physiologic daily dosing of steroids is allowed. Nasal, or inhaled steroid, topical steroid creams and eye drops for small body areas are allowed.
  * Patients who have undergone allogeneic peripheral stem cell transplantation, or solid organ transplantation requiring immunosuppression
* Pregnant women are excluded from this study because M7824 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M7824 breastfeeding should be discontinued if the mother is treated with M7824. These potential risks may also apply to other agents used in this study.
* Patients with active systemic autoimmune disease, except patients with type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current immunosuppression, or with other endocrine disorders on replacement hormones, are not excluded if the condition is well controlled.
* Patients with a history of inflammatory bowel disease
* Patients with a history inflammatory lung disease/interstitial lung disease/pulmonary fibrosis will be excluded. Patients with clinical findings (e.g., imaging) that are suggestive of inflammatory lung disease even if not experiencing symptoms of the disorder.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents to be used in the cohort the subject will be enrolled into.
* Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or tobramycin). Patients enrolling on the M7824 only arm will be exempt from this exclusion.
* Patients with a history of bleeding diathesis or recent clinically significant bleeding events considered by the Investigator as high risk for investigational drug treatment are excluded.
* Any condition which, in the opinion of the investigator, would prevent full participation in this trial (including the long-term follow-up), or would interfere with the evaluation of the trial endpoints.
* Patients with prior live vaccine, investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to enrollment. Locally approved coronavirus disease (COVID) vaccines are permitted.
* Uncontrolled intercurrent acute or chronic illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (\>New York Heart Association Class I), hepatic disease, unstable angina pectoris, serious cardiac arrhythmia, requiring medication, uncontrolled hypertension (systolic blood pressure (SBP\>170/ diastolic blood pressure (DBP\>105) or psychiatric illness/social situations within 12 months that would limit compliance with study requirements.
* Patients who have undergone major surgery within 4 weeks prior to enrollment. A biopsy will not preclude a patient from starting study.
* Patients with a history of hepatitis B (HBV) are excluded due to potential risk for viral reactivation and resulting liver injury in persons with latent HBV.
* Patients with treated or active brain metastases are not eligible because we are enrolling non-metastatic head and neck cancer patients in this trial. Standard of care treatment is different for head and neck cancer patients with and without metastatic disease.
* Subjects unwilling to accept blood products as medically indicated.