Adjuvant De-Escalated Radiation + Adjuvant Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer

Inclusion Criteria:

* Age \>/= 18 years.
* ECOG performance status of 0 or 1.
* Patients must have newly diagnosed, histologically or cytologically confirmed squamous cell carcinoma or undifferentiated carcinoma of the oropharynx. Patients must have been determined to have resectable oropharyngeal disease. Patients with primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not eligible.
* Patients must have intermediate risk factors, as described below as determined by imaging studies (performed \< 45 days prior to registration) and complete neck exam, from the skull base to the clavicles. The following imaging is required: CT scan of neck only with IV contrast or MRI. PET scan of HN and chest with IV contrasted CT correlation is encouraged prior to enrollment.

Intermediate risk features: Tobacco \<10 pk-yr: T0-3 plus any one of the following: \>N2b (\> 5 LN's +), N2c/N3, +ENE \>1 mm, or + margin (if approved by surgical chair) OR Tobacco \>10 pk-yr: T0-3 plus any one of the following: any N2, N3, +ENE \>1 mm, or + margin (if approved by surgical chair)

* Patients must have no evidence of distant metastases (M0)
* Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of invasive squamous cell carcinoma may have been obtained from the primary tumor or metastatic lymph node. It is required that patients have a positive p16 IHC (as surrogate for HPV) status from either the primary tumor or metastatic lymph node.
* Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (IHC) performed by a CLIA approved laboratory.
* No prior radiation above the clavicles.
* Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix, differentiated thyroid cancer, melanoma in-situ (if fully resected), and/or non-melanomatous skin cancer, or clinically negligible in judgement of investigator.
* Patients with the following within the last 6 months prior to registration must be evaluated by a cardiologist and / or neurologist prior to entry into the study.

  * Congestive heart failure \> NYHA Class II
  * CVA / TIA
  * Unstable angina
  * Myocardial infarction (with or without ST elevation)
* Patients must have acceptable renal and hepatic function within 4 weeks prior to registration as defined below:

  * Absolute neutrophil count ≥1,500/mm3
  * Platelets ≥ 100,000/mm3
  * Total bilirubin ≤ the upper limit of normal (ULN)
  * Calculated creatinine clearance must be \> 60 ml/min using the Cockcroft-Gault formula: (140-age)\*wt(kg)/(\[Cr\]\*72). For women the calculation should be multiplied by 0.85
* Women must not be pregnant or breast-feeding. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
* Patient without intercurrent illness likely to interfere with protocol therapy.
* Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to registration.

Exclusion Criteria:

* Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
* Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted to enroll.
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone 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.
* Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
* Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 30 days of first administration of study treatment (subjects with prior radiation, cytotoxic or investigational products \< 4 weeks prior to treatment might be eligible after discussion between investigator and sponsor, if toxicities from the prior treatment have been resolved to Grade 1 (NCI CTCAE version 4).
* Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Subjects who test positive for HCV antibody but negative for HCV ribonucleic acid are permitted to enroll.
* Known history of testing positive for human immunodeficiency virus (HIV) and CD4 count \< 200 or known acquired immunodeficiency syndrome (AIDS).
* Any Grade 4 laboratory abnormalities.
* History of allergy to study drug components.
* History of severe hypersensitivity reaction to any human monoclonal antibody.
* Prisoners or subjects who are involuntarily incarcerated.
* Subjects compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.