Immunogenicity and Biomarker Analysis of Neoadjuvant Ipilimumab for Melanoma

Inclusion Criteria: * Willing and able to give written informed consent. * Histologic diagnosis of melanoma belonging to T1-4 N1b,2b,2c,3 M 0 AJCC stages, that may present as any of the following groups: * Primary melanoma with clinically apparent (overt) regional lymph node metastases, confirmed by pathological diagnosis (biopsy). * Clinically detected recurrence of melanoma at the proximal regional lymph node(s) basin, confirmed by pathological diagnosis (biopsy). * Clinically or histologically detected primary melanoma involving multiple regional nodal groups, confirmed by pathological diagnosis (biopsy). * Clinically detected single site of nodal metastatic melanoma arising from an unknown primary, confirmed by pathological diagnosis (biopsy). * Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal metastasis, or at the time of clinically detected nodal recurrence. Patients must undergo biopsy (punch) or open biopsy (if done as part of a clinically indicated baseline diagnostic procedure) within 14 days of entry into the study. Lymphadenectomy will be performed after at least 2 and generally not longer than 4 weeks of ipilimumab therapy. Additional delays for definitive lymphadenectomy are allowed if clinically indicated while awaiting the resolution of potential adverse events from ipilimumab therapy. * Patients must have been evaluated by standard-of-care full body imaging studies (CT, PET-CT or MRI) as part of the initial clinical work-up at baseline (no more than 4 weeks prior to study enrollment) and after completion of 2 doses of ipilimumab (at 6-8 weeks after the first dose of ipilimumab and prior the definitive lymphadenectomy procedure). * Required values for initial laboratory tests: * White Blood Cell ≥ 3000/uL * Absolute Neutrophil Count ≥ 1500/uL * Platelets ≥ 100 x 103/uL * Hemoglobin ≥ 10 g/dL * Creatinine ≤ ULN * AST/ALT ≤ 2.5 x Upper Limit of Normal (ULN) * Bilirubin ≤ ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL) * PT/PTT ≤ ULN (No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.) * Adequate performance status (ECOG 0, 1). * Men and women, ≥ 18 years of age. * Women of childbearing potential (WOCBP) must be willing to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of ipilimumab. WOCBP include any female who has experienced menarche and who has not undergone a successful surgical sterilization procedure (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as: * Amenorrhea ≥ 12 consecutive months without another cause, or * For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL. * Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab. Exclusion Criteria: * Patients with clinical, radiological/laboratory, or pathological evidence of distant metastatic disease. * Patients with evidence of soft tissue involvement by gross extranodal extension of tumor manifest by fixation to the fascia, or matting of nodal tissue that would compromise surgical resection as determined by the surgical oncologist. * Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation. * Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix. * Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[eg, Wegener's Granulomatosis\]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome). * Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea. * Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult. * Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab). * A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or agonist. * A history of prior radiotherapy, chemotherapy, including infusion or perfusion therapy for his current disease or any immunotherapy including tumor vaccines, interferon-alfa, interleukins, levamisole or other biologic response modifiers within the past 4 weeks. * Concomitant therapy with any of the following: IL 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; unless discontinued ≥ 4 weeks. * Women of childbearing potential (WOCBP), defined above in Section 4.1, who: * are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or * have a positive pregnancy test at baseline, or * are pregnant or breastfeeding. * Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness. Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study participation and the potential risk factors for an unintentional pregnancy. All WOCBP MUST have a negative pregnancy test before first receiving ipilimumab. If the pregnancy test is positive, the patient must not receive ipilimumab and must not be enrolled in the study.