oTumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or suspected tumor. oAny drug-related amylase or lipase abnormality that is not associated with symptoms or clinical manifestations of pancreatitis. oHgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or erythroid growth factor use does not require treatment discontinuation. oKeratoacanthoma and squamous cell carcinoma of the skin. oAny endocrinopathy that can be medically managed with hormone replacement oThose which in the opinion of the investigator is not clinically relevant or can be medically managed with minimal risk to the patient (e.g. placement of a pleurx catheter for recurrent inflammatory pleural effusions) 3.3.4 Dose hold Dose hold determined to be necessary by the investigator is permitted. If a patient misses the 2nd dose of M7824 that patient does not need to be replaced on that study arm. For conditions determined to be transient by the principal investigator, treatment may be delayed by up to 3 days. N-803 dosing should be held for hypotension (defined as systolic blood pressure less than 90 mm Hg) if in the presence of any clinically significant symptoms (in the opinion of the treating physician), until the systolic blood pressure reading is stable. If mild dehydration is suspected, an IV fluid bolus may be used per standard of care. 33 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 3.4 STUDY CALENDAR Procedure Screening Baseline1D1 D8 D15 D21- 2821D49 D29- 10414D10515Long Term FU16 NIH Advance Directive Form2X Evaluations Physical exam, weight and ECOGX X X18X17X Radiologic Evaluation3X X X Histologic confirmation of dx X Medical history X X X18X17X Height X EKG X Vital Signs X X X X18X17X Biopsies Pre-treatment biopsy (mandatory)5X Post-treatment biopsy (optional)6X 34 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Procedure Screening Baseline1D1 D8 D15 D21- 2821D49 D29- 10414D10515Long Term FU16 Clinic-based flexible nasopharyngo-laryngoscopy and/or tracheoscopy19X X X X X Study Agents M78247X X ETBX 011, 051, and 0618X N-8039X Taken off treatment for definitive surgical resection*X Laboratory tests CBC w/differential, PT, PTT X X X18X20X17X Chemistry10X X X18X17X Amylase, lipase, LDH, GGT, X X18X17X CK, Uric Acid, Total Protein, CRPX X18X17X Thyroid tests-TSH, free T3 & T4X X18X17X TBNK phenotyping X 35 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Procedure Screening Baseline1D1 D8 D15 D21- 2821D49 D29- 10414D10515Long Term FU16 HIV, Hepatitis B and C serology and/or viral loadX Serum pregnancy test11X X HLA Class I 12X Urinalysis X X X18X Correlative Studies (Please refer to section 5.1 for details) Research blood 13X X X X X Follow-up and others Adverse event evaluation X X X X Concomitant meds X X X X Phone call or e-mail every two weeksX Phone call or e-mail every 3 months17X *Resection will be planned and performed under the care of surgeons as per standard of care once patients are taken off of study treatment. The records from outside providers administering standard of care surgery and anti- cancer therapies will be requested in reviewed . For patients that have surgery outside of the NIH Clinical Center, tissue 36 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 blocks and/or slides will be obtained from the institution where the patient underwent surgery after the patient signs that institution’s release document. 1.Baseline evaluations do not need to be repeated if performed within given time frame.