Trial of Nivolumab as a Novel Neoadjuvant Pre-Surgical Therapy for Locally Advanced Oral Cavity Cancer

Inclusion Criteria: 1. Newly diagnosed histologically proven locoregional OCSCC without evidence of distant metastases and a clinically determined T-stage of 2-4, OR Recurrent or persistent histologically proven locoregional OCSCC that was initially treated with surgery alone, and a clinically determined recurrent T-stage of 2-4. Note - OCSCC includes the subsites of oral tongue, floor of mouth, gingiva, retromolar trigone, and buccal mucosa. Note - To allow sufficient tumor tissue for the immunological analyses, patients with T-stage 1 OCSCC will be excluded 2. Greater than or equal to 18 years of age 3. ECOG performance status of 0 or 1 4. Screening labs must meet the following criteria and must be obtained within 14 days prior to registration: * WBC \> 2,000/µL * Absolute Neutrophil Count \>1,500/µL * Platelets \> 100 X 103/µL * Hemoglobin \> 9.0 g/dL * Serum creatinine \< 1.5 X ULN or CrCl \> 40mL/min (if using the Cockcroft-Gault formula below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL * AST/ALT ≤ 3 x ULN * Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) 5. Reproductive Status: WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception with a failure rate of less than 1% per year for a period of 31 weeks after the last dose of investigational product. WOCBP 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 consecutive months of amenorrhea in a woman over 45. Women of childbearing potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to registration Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men, are not required to use contraception. Exclusion Criteria: 1. Prior immunotherapy or treatment with another anti PD 1 agent 2. Prior chemotherapy including Cetuximab or radiation therapy 3. Previous severe hypersensitivity reaction to another monoclonal antibody 4. Women who are pregnant, lactating or expecting to conceive 5. Men who are expecting to father children within the research period 6. Known history of HIV or AIDS 7. Positive test for HBV sAg or HCV antibody indicating acute or chronic infection 8. Concomitant malignancies except cutaneous squamous cell carcinoma or basal cell carcinoma 9. Unresectable primary tumor or regional disease; presence of distant metastases. 10. History of pneumonitis or interstitial lung disease 11. Active, known or suspected autoimmune disease. Note: Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger 12. Presence of condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease