HPV-16 Vaccination and Pembrolizumab Plus Cisplatin for "Intermediate Risk" HPV-16-associated Head and Neck Squamous Cell Carcinoma

Inclusion Criteria

• Histologically-confirmed head and neck squamous cell carcinoma with no evidence of distant metastasis, with a primary site being the oropharynx. Squamous cell carcinoma of unknown primary, metastatic to cervical lymph nodes - patients can enroll provided all other eligibility criteria are met.
• Patients must have intermediate risk disease.

o Patients must meet one of the following criteria: Oropharynx: p16(+) PLUS HPV ISH(+) (DNA or RNA) AND one of the following; ≥ AND ≥ 10 pack-years tobacco exposure (see Tobacco Assessment Form, Appendix A)

• T4 or N2c/N3 disease irrespective of tobacco exposure
• Unknown primary: p16(+) PLUS HPV ISH(+) (DNA or RNA) AND one of the following
• ≥ N2a AND ≥ 10 pack-years tobacco exposure
• N2c/N3 disease irrespective of tobacco exposure
• Patients should be considered not a candidate for curative-intent surgery with diagnosis of AJCC 7th edition Stage III, IVa, or IVb disease.
• Diagnostic simple palatine or lingual tonsillectomy is permitted, provided patient has RECIST-measurable nodal disease.
• Patients with a second HNSCC primary tumor are eligible for this study, provided more than 2 years have elapsed since the first diagnosis of HNSCC, the original tumor was managed with surgery only (no adjuvant chemotherapy or radiotherapy), and has not recurred.
• Patients with simultaneous primaries are excluded, with the exception of patients with bilateral tonsil/base of tongue HPV+ cancers or patients with T1-2, N0, M0 differentiated thyroid carcinoma (resected or management deferred), who are eligible.
• No prior systemic (chemotherapy or biologic/molecular targeted therapy) or radiation treatment for head and neck cancer.
• Patients may have received chemotherapy or radiation for a previous, curatively treated non-HNSCC malignancy, provided at least 2 years have elapsed.
• Patients must be untreated with radiation above the clavicles.
• Patients with a history of curatively-treated non-HNSCC malignancy must be disease-free for at least 2 years except for excised and cured disease.
• The patient must undergo a mandatory research biopsy at baseline. There will be 2 other optional biopsies that the patient will be asked to consent to, the first is durking week 2 of pembrolizumab/ISA101b vaccination (prior to start of cisplatin-IMRT-this correlates to week (-)1), the second once will be during week 2 after the start of IMRT (this correlates to week 1).
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Age ≥ 18
• Patients must have measurable disease according to RECIST 1.1
• Patients must demonstrate adequate organ function
• Written informed consent must be obtained from all patients prior to study registration.
• Documentation of negative pregnancy within 10 days of treatment initiation.

Exclusion Criteria

• Oral Cavity, Larynx, Hypopharynx or Nasopharyngeal primary site
• Current participation in or previous participation in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment.
• Prior treatment with anti-HPV agents except prevention HPV vaccines
• History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agents (pembrolizumab and ISA101b
• Distant metastatic disease including CNS or leptomeningeal metastases is not allowed.
• Acquired Immune Deficiency Syndrome (AIDS).
• Received prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• History of second malignancy within 2 years prior to Study Day 1 (except for excised and cured non-melanoma skin cancer, carcinoma in situ of breast or cervix, superficial bladder cancer, or T1a or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen (PSA) since resection).
• Active autoimmune dis