Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers

Prior treatment

• Participants cannot have used any other investigational agents within the previous six months
• Prior chemotherapy or thoracic radiation within the past 1 year
• History of interstitial pneumonitis requiring treatment with systemic corticosteroids or other immunosuppressive agents (e.g., mycophenolate, azathioprine)
• Pneumonia or acute bronchitis for at least 2 weeks prior to enrollment

Other illness

• Patients cannot receive any other investigational anti-cancer agents while participating in the study
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab
• Cardiac dysrhythmia that is potentially life-threatening, such as ventricular tachycardia, multifocal premature ventricular contractions or supraventricular tachycardias with a rapid ventricular response. Well-controlled atrial fibrillation or rare (\< 2 minute) premature ventricular contractions are not exclusionary
• Individuals who are HIV-positive will be considered on a case-by-case basis, but will be required to meet criteria related to patient safety and data integrity, as assessed by the study investigators
• History of hepatitis B or hepatitis C infection that is untreated and/or with a detectable viral load
• Severe obstructive lung disease (GOLD Stage III or IV, FEV1\<30% predicted)
• Participants with findings on CT chest suspicious for lung cancer (Lung-RADS category 4) will not be allowed to enroll until they have undergone additional evaluation for malignancy and an alternative (i.e., non-malignant) diagnosis has been established
• Current malignancy, with the exception of non-melanoma (i.e., basal cell or squamous cell) skin cancer. Patients with lung carcinoma in situ found during the study biopsy are also excluded.
• History of a malignancy except for adequately treated non-melanoma (i.e., basal cell or squamous cell) skin cancer or in situ cervical cancer for which the subject has not been disease-free for 5 years. Patients with a history of non-small cell lung cancer (stage I, II, or IIIA) or head and neck cancer (stage I, II, III, or IVA) must have no evidence of active disease at least 1 year after definitive treatment.
• History of stage IIIA NSCLC for which the only treatment was chemoradiation without surgery
• Known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll
• Conditions requiring systemic corticosteroids equivalent to \> 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of enrollment
• Known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity

Lab values

• Participants may not be currently receiving immune checkpoint inhibitor treatment or have been treated with immune checkpoint inhibitors in the past (including anti-programmed cell death receptor \[PD\]-1, anti-programmed death ligand 1 \[PD-L1\], and anti-cytotoxic T-lymphocyte associated protein 4 \[CTLA4\] monoclonal antibodies)
• Clinically apparent bleeding diathesis (i.e., bleeding that is spontaneous, excessive, or delayed in onset following tissue injury results from a localized pathologic process or a disorder of the hemostatic process, involving a complex interplay among vascular integrity, platelet number and function, coagulation factors, and fibrinolysis)
• History of coronary artery disease, including myocardial infarction, congestive heart failure (LV ejection fraction \<50% or clinically significant diastolic dysfunction), or any serious medical condition which would preclude a patient from undergoing a bronchoscopy or would jeopardize the goals of the study
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 4 weeks prior to the start of nivolumab

Other

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Hypoxemia (less than 90% saturation with supplemental oxygen)
• Life expectancy of \< 1 year
• Women must not be breastfeeding
• Inability to give informed consent

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female, aged \> 18 years
• A current or ex-smoker with a \> 30 pack-year history of smoking and mild or worse sputum cytologic atypia or known bronchial dysplasia, OR history of non-small cell lung cancer (stage I, II, or IIIA) with \> 10 pack-year history of smoking and no evidence of active disease at least 1 year after definitive treatment, OR history of head and neck cancer (stage I, II, III, or IVA) with \> 10 pack-year history of smoking and no evidence of active disease at least 1 year after definitive treatment. An ex-smoker is defined as no tobacco use in the prior 12 months
• Endobronchial dysplasia (score \> 4) on screening bronchoscopy
• Total granulocyte count \> 1500
• Platelet count \> 100,000
• Serum creatinine \< 1.5 mg/dL
• Total bilirubin \< 2.0 mg/dL
• Transaminases and alkaline phosphatase \< 2.5x upper limit of normal
• Albumin \> 2.5 mg/dL
• ECOG performance status ≤ 1
• Participants must be able and willing to undergo three bronchoscopies: before, after four doses of nivolumab (8 weeks), and after 6 months