Neoadjuvant Targeting of Myeloid Cell Populations in Combination With Nivolumab in Head & Neck Ca

Inclusion Criteria:

• The primary site should be a head and neck squamous cell carcinoma (including, butnot limited to oral cavity, oropharynx, hypopharynx, or larynx, paranasal sinuses,nasal cavity). Squamous cell carcinoma of unknown primary, diagnosed in lymph nodesin neck, can be included but should be tested for p16 and confirmed with an HPVspecific assay (testing NOT required for enrollment; can be done at an interval).

• Subjects must be human papillomavirus (HPV) negative (confirmed testing fororopharyngeal primary tumors - if otherwise suspected HPV positivity e.g. some oralcavity or sinonasal tumors if e.g. absence of smoking) OR (if HPV+) be high riskbased on a ≥20 pack year smoking history.

• HPV testing is required per clinical standards

• Subjects must have been determined to be candidates for surgical resection by amultidisciplinary team including a surgeon, a medical oncologist and a radiationoncologist. Resection should typically be definitive but may also be done forsymptomatic control e.g. in the setting of (suspected) metastatic disease withdominant local symptoms.

• Subjects must have at least one lesion that can be (or has been) biopsied atbaseline.

• Patients with metastatic disease (both HPV(-) and high-risk HPV(+) (i.e. ≥20 packyears of smoking) are allowed, as long as patients have an indication for surgeryfor locoregional disease, and a life expectancy of ≥6 months. Metastatic disease canbe addressed with additional treatments after trial treatment, e.g. focal radiation,or additional systemic therapy (e.g. chemotherapy or as indicated a targeted therapyor standard of care immunotherapy).

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1

• Age greater than or equal to 18 years

• Life expectancy of greater than 6 months

• Patients must have normal organ and marrow function

• The effects of nivolumab, as well as the other agents in this study on thedeveloping human fetus are unknown.

• Women of childbearing potential (WOCBP) must have a negative urine or serumpregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment.

• Women must not be breastfeeding

• Women of childbearing potential (WOCBP) must agree to follow instructions formethod(s) of contraception as outlined in protocol

• Males who are sexually active with WOCBP must agree to follow instructions formethod(s) of contraception as outlined in protocol

• Patient understands the study regimen, its requirements, risks and discomforts andis able and willing to sign the informed consent form. Voluntary signed and datedInstitutional Review Board (IRB) approved written informed consent form inaccordance with regulatory and institutional guidelines must be obtained before theperformance of any protocol related procedures that are not part of normal patientcare. Subjects must be competent to report AEs, understand the drug dosing scheduleand use of medications to control AEs

• Measurable disease - either radiologically (per RECIST) or clinically measurable onexam in order to assess treatment response.

Exclusion Criteria:

• Any active history of a known autoimmune disease. Subjects with vitiligo, type 1diabetes mellitus, residual hypothyroidism requiring hormone replacement, orconditions not expected to recur in the absence of an external trigger are permittedto enroll.

• Patients who received prior therapy with anti programmed death-1 (PD-1), anti-PD-L1,anti-PD-L2, anti CD137, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4),anti-CSF1R, anti-interleukin-8 (IL8) therapies, any other antibody or drugspecifically targeting T-cell co-stimulation or checkpoint pathways.

• Any live / attenuated vaccine (e.g. varicella, zoster, yellow fever, rotavirus, oralpolio and measles, mumps, rubella (MMR) etc.) within 30 days of first dose of studytreatment.

• Patients with uncontrolled brain metastases

Patients with brain metastases must have stable neurologic status following local therapy (surgery and/or radiation) for at least 2 weeks without the use of steroids or on stable or decreasing dose of ≤ 10mg daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of carcinomatous meningitis are not eligible.

However, patients with metastatic disease (both HPV(-) and high-risk HPV(+) (i.e. ≥20 pack years of smoking) are allowed, as long as patients have an indication for surgery for locoregional disease, and a life expectancy for ≥6 months. Metastatic disease can be addressed with additional treatments after trial treatment, e.g. focal radiation, or additional systemic therapy (e.g. chemotherapy or as indicated a targeted therapy or standard of care immunotherapy).

• Patients who have an active concurrent malignancy that is not controlled/cured andcould impact life expectancy within the next 3 years. E.g. patients with localizedcutaneous squamous cell carcinoma or basal cell carcinoma or treated prostate cancerwith no evidence of disease progression may be allowed to enroll after review by thestudy team and principal investigator.

• Uncontrolled inter-current illness including, but not limited to, no clinicallysignificant active infection requiring (antimicrobial) treatment in the last week,symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiacarrhythmia, myocardial infarction or new onset angina within six months ofenrollment, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Women who are pregnant or nursing

• Men with female partners who are not willing to use contraception (Contraceptionmethod defined in protocol)

• Active infection with hepatitis B or hepatitis C (active infection is defined byeither a) abnormal liver function tests (=elevated aspartateaminotransferase/alanine aminotransferase) or b) ongoing use of an antiviralhepatitis treatment).

• Patients with normal liver function tests (=normal aspartateaminotransferase/alanine aminotransferase) and no antiviral medication perdefinition do not have an active infection and are eligible to enroll withoutadditional testing).

• Patients with normal liver function test do NOT need additional Hepatitis (noneed for Hepatitis serology and/or PCR)

• Patients with a condition requiring chronic systemic treatment with eithercorticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressivemedications within 14 days of study start. However, inhaled or topical steroids andadrenal replacement steroid doses < 10 mg daily prednisone equivalent, are permittedin the absence of active autoimmune disease. Also, a burst of steroids (≤10 daysuse, e.g. a contrast premedication, or a methylprednisolone dose pack or similar)are acceptable and not excluded.

• Epstein-Barr Virus (EBV) positive head and neck cancer (e.g. EBV(+) nasopharyngealcarcinoma)

• Patients with HIV are excluded given the unknown risk of interaction with HAART andthe unknown benefit of immunotherapy in this population.