Inclusion Criteria:
* Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
* Age 18 years and older at the time of registration consent
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 within 30 days prior to enrollment
* Suspected clinical American Joint Committee on Cancer (AJCC) 8th edition stage II-IVB (T2-T4b N0-N3) oral cavity cancer (oral tongue, floor of mouth, buccal, gingival, retromolar trigone, lip, hard palate) amenable to surgical resection. Patients will be consented prior to research biopsy.
* Primary tumor of at least 2 cm which is amenable to a 250 mm3 (e.g.10 mm x 5 mm x 5 mm) research biopsy, equivalent to one-two forceps biopsies.
* Patients may not have received prior chemotherapy or immunotherapy for the oral cavity malignancy. Patients must have completed other cancer therapies unrelated to their oral cavity cancer greater than 30 days prior to enrollment.
* Participants of childbearing potential must agree to contraception during and for 100 days after study therapy.
* Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to treatment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for \> 12 consecutive months.
* Demonstrate adequate organ function
Exclusion Criteria:
* Subjects with a diagnosed auto-immune disease (exceptions: subjects with controlled diabetes mellitus type I, thyroid disease, rheumatoid arthritis, vitiligo and alopecia areata not requiring treatment with immunosuppressants are eligible)
* Pregnant or breastfeeding
* Known additional invasive malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease free for at least three years prior to enrollment. This excludes the index oral cavity cancer.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor.
* Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to randomization/allocation.
* Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
* Has had previous allogeneic tissue/solid organ transplant.
* Subjects who require systemic treatment doses of corticosteroids (prednisone equivalent greater than or equal to 10 mg daily), or other immunosuppressive drugs
* Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review
* Has Grade 3-4 bleeding due to the underlying malignancy
* Subjects with known human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or hepatitis C infection based on medical history. No testing for HIV, Hepatitis B, or Hepatitis C is required for enrollment. Subjects cannot be positive for HBV DNA, HCV RNA, hepatitis B surface antigen, or anti-hepatitis B core antibody. Patients with Hepatitis B surface antigen negative and anti-hepatis B core antibody positive with undetectable HBV DNA by polymerase chain reaction may enroll.
* Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
* Subjects who cannot provide independent, legal, informed consent
