This phase II trial studies how well nivolumab, carboplatin, and paclitaxel work in treating patients with stage III-IV head and neck squamous cell carcinoma that can be removed by surgery. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab, carboplatin, and paclitaxel may work better in treating patients with head and neck squamous cell carcinoma.

PRIMARY OBJECTIVES:

I. To estimate pathologic complete response (pCR) at the primary site in patients with newly diagnosed and untreated stage III-IVA squamous cell carcinoma of the head and neck (SCCHN) of the oral cavity, oropharynx, larynx, and hypopharynx with nivolumab, paclitaxel and carboplatin in addition to standard chemotherapy.

SECONDARY OBJECTIVES:

I. Safety. II. Complete pathologic response at all sites of disease. III. Major pathologic response rate at primary site. IV. Overall clinical response rate. V. Clinical complete response rate. VI. 1 year progression-free survival (PFS). VII. Overall survival.

TERTIARY OBJECTIVES:

I. To explore whether PDL1 expression is associated with treatment response. II. To explore whether there is a net change in the Th1/Th2 ratio (IFN-gamma, IL-4, IL10, etc.) or cell subset frequencies (M2 monocytes, myeloid-derived suppressor cells, etc.) within a patient's peripheral blood either at baseline or in response to treatment is associated with treatment response.

III. To explore whether exosomes or other immune related serum biomarkers change after combination therapy.

IV. To explore the predictive value of serial cell free deoxyribonucleic acid (DNA) levels and response.

Inclusion Criteria:

• Patients must be 18 years of age and older.
• Pathologically confirmed SCCHN, not previously treated, with a plan to undergo surgery
• Patients who have stage III-IV disease without distant metastases (M0) of 1) oral cavity, 2) larynx, 3) hypopharynx 4) oropharynx (human papillomavirus [HPV] neg) using American Joint Committee on Cancer (AJCC) 8th edition
• Patients who have oropharyngeal cancer that HPV positive, stage II-III disease without distant metastases (M0) using AJCC 8th edition
• All patients with oropharyngeal SCCHN must be tested for HPV (by p16 and/or HPV in situ hybridization [ISH] or polymerase chain reaction [PCR])
• Patients must be evaluated by a head and neck surgeon and be deemed surgically resectable at baseline
• Tumor sample must be available for HPV p16 and PD-L1 testing and if oropharyngeal, must be tested for HPV p16
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• While blood cells 2000/ul or more
• Absolute neutrophil count 1500/ul or more
• Platelets 100,000/ul or more
• Hemoglobin 9 g/dl or more; (transfusion permitted)
• Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with Gilbert syndrome, who can have total bilirubin < 3 mg/dl)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x the upper limit of normal
• Glomerular filtration rate (GFR) greater than or equal to 40 ml/min using the Cockcroft-Gault formula or serum creatinine less than or equal to 1.5 x upper limit of normal (ULN)
• Women of reproductive potential should have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 21 days of study enrollment
• Women of reproductive potential must use highly effective contraception methods to avoid pregnancy for 23 weeks after the last dose of study drugs; "women of reproductive potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
• Men of reproductive potential who are sexually active with women of reproductive potential must use any contraceptive method with a failure rate of less than 1% per year; men who are receiving the study medications will be instructed to adhere to contraception for 31 weeks after the last dose of study drugs; men who are azoospermic do not require contraception
• All subjects must be able to comprehend and sign a written informed consent document

Exclusion Criteria:

• Primary nasopharyngeal carcinoma
• Patients who have participated in a study with an investigational agent or device within 2 weeks of initiation of treatment
• Any prior radiotherapy to the neck
• Any prior treatment for SCCHN
• Any prior therapy with anti-PD-1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Any history of a sever hypersensitivity reaction to any monoclonal antibody
• Any history of allergy to the study drug components
• Any concurrent malignancies- exceptions include- basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer that has undergone potentially curative therapy; patients with a history of other prior malignancy must have been treated with curative intent and must have remained disease-free for 3 years post-diagnosis
• Any diagnosis of immunodeficiency or current immunosuppressive therapy including >10mg/day of prednisone within 14 days of enrollment is not permitted (excludes emergency transient steroid use at discretion of the treating physician).
• Patients that have an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids (> 10 mg daily prednisone equivalents) or immunosuppressive agents. Subjects with vitiligo, type I diabetes mellitus, or resolved childhood asthma/atopy would be an exception to this rule. Inhaled or topical steroids, and adrenal replacement steroid doses ≤10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
• Patients with a known human immunodeficiency virus infection (HIV 1/2 antibodies) or acquired immunodeficiency syndrome (HIV/AIDS), active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Patients with evidence of non-infectious pneumonitis or history of interstitial lung disease
• Patients who have received a live vaccine within 30 days prior initiation of the systemic regimen
• Patients must not be receiving any other investigational agents
• Patients with uncontrolled intercurrent illnesses including, but not limited to an active infection requiring systemic therapy or a known psychiatric or substance abuse disorder(s) that would interfere with cooperation with the requirements of the trial
• Women must not be pregnant (as above) or breastfeeding