Should the participant continue to be unreachable, he or she will be considered to have withdrawn from the study with a primary reason of lost to follow-up. 4 CONCOMITANT MEDICATIONS/MEASURES 4.1 GENERAL GUIDANCE Supportive care with blood components, antibiotics, analgesics, general medical therapy, etc., will be delivered as required. Immunotherapy including interferon, immunosuppressive drugs (for example, chemotherapy or systemic steroids except for short term treatment of allergic reactions, endocrine replacement therapy or low dose prednisone [≤ 10mg daily] or equivalent, or for the treatment of irAEs or other appropriate short-term steroid use), or other experimental pharmaceutical products are prohibited. Short term administration of systemic steroid or other immunosuppressant such as infliximab or mycophenolate (that is, for allergic reactions or management of irAEs) is allowed. Steroids with no or minimal systemic effect (topical, inhalation), are allowed. Any live vaccine therapies for the prevention of infectious disease are prohibited. Administration of inactivated vaccines is allowed (for example, inactivated influenza vaccine). Locally approved COVID vaccines are permitted. Antiemetics may be used for the treatment of nausea and vomiting but should not be used prophylactically at first dosing. Steroid-based anti-emetics are not allowed. 4.2 N-803 Central nervous system function may be affected with N-803. Caution should be used with psychotropic medications. Nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic medications should be avoided if possible as they may further increase toxicities that have been associated with N-803. Interferon-alfa is prohibited while on study. Beta-blockers and other antihypertensives may potentiate the hypotension seen with N-803. Therefore, administration of these agents should be avoided during N-803 treatment period, unless clinically indicated. If a patient who is to receive N-803 is on a beta-blocker or other antihypertensive, that agent may be discontinued starting on the day of the first treatment with N- 803, if the investigator determines that stopping the agent is safe. The beta blocker may be resumed 2 weeks following the dose of N-803. Anti-hypertensive management decisions will be made on a case by case basis. For example, an anti-hypertensive may be resumed or added at any point if the investigator believes it to be clinically indicated e.g. if a patient experiences uncontrolled hypertension while receiving N-803 treatment on study. For patients on antihypertensives at baseline, the agent will be resumed if clinically indicated by blood pressure readings in the days following N-803 treatment cessation. If a localized skin rash at the injection site occurs that is >6 cm and symptomatic, it may be treated with 0.05% clobetasol propionate or 0.1% triamcinolone cream or similar product at the discretion of the treating physician. 40 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Administration of additional glucocorticoids is discouraged during the N-803 treatment period as the use of systemic steroid medications may result in loss of therapeutic effects of the study drug. However systemic steroids may be used to treat an irAE. 41 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 5 BIOSPECIMEN COLLECTION 5.1 CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC S TUDIES Study Test Name Lab Name Sample Time PointsVolume/type Tube* Visualization of immune cells and analysis of immune cell localization 5.1.1Multiplex immunofluore scenceTIML, GMB, Dr. Houssein SaterD1 and D21-28 or at surgeryFixed tumor tissue N/A T cell receptor (TCR) sequencing 5.1.2 Deep-TCR sequencingFrederick Genomic Core Facility, Dr. Xiaolin WuD1 and D21-28 or at surgeryFixed tumor tissue N/A Assessment of antigen-specific responses in TIL 5.1.3 RNA-Seq Sample Preparation in Allen Lab and sequencing at NantD1 and D21-28 or at surgeryFresh tumor tissue N/A Exome sequencing, RNA sequencing and neoantigen prediction 5.1.3 DNA and RNA sequencingNant D1 and D21-28 or at surgeryFixed tumor tissue N/A Biomarker analysis related to wound healing 5.1.4 Expression analysisAllen Lab D1 and D21-28 or at Snap frozen tumor, normal mucosa and N/A 42 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 surgery skin tissue may also be sampled Sorting and expansion of B cells to be used as antigen presenting cells for assays 5.1.3FACS sorting Allen Lab D1, 8, 15, 21-28, D105Whole blood for PBMC Assessment of antigen-specific responses in peripheral T cells. 5.1.5Intracellular cytokine staining assayDr.