Intralesional Influenza Vaccine for the Treatment of Stage I-IV Melanoma

Inclusion criteria

• Males or females
• 18 to 99 years of age
• Histologically confirmed cutaneous melanoma by historical pathology report review, clinical Stage I-III (Cohort #1), or Stage IV (Cohort #2) cutaneous melanoma
• At least one, biopsy-proven, palpable melanoma tumor deposit suitable for intralesional injection measuring ≥ 1 cm by digital caliper (with digital photography documentation) or ultrasound (with ultrasound image documentation)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• Absolute neutrophil count (ANC) \>= 1.5 x 10\^3/mm\^3 (drawn at or not more than 30 days prior to the screening visit)
• Hemoglobin (Hgb) \>= 8 g/dL (drawn at or not more than 30 days prior to the screening visit)
• Platelet count \>= 100 x 10\^3/mm\^3 (drawn at or not more than 30 days prior to the screening visit)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN) or =\< 5 x ULN in patients with liver metastases (Cohort 2 only) (drawn at or not more than 30 days prior to the screening visit)
• Prothrombin time =\< 1.5 x ULN (drawn at or not more than 30 days prior to the screening visit)
• Total bilirubin =\< 1.5 x ULN (unconjugated bilirubin of \< 3 x ULN for patients with known Gilbert syndrome) (drawn at or not more than 30 days prior to the screening visit)
• Creatinine clearance of \>= 50 ml/min by Cockcroft-Gault equation (drawn at or not more than 30 days prior to the screening visit)
• Women of childbearing potential (WOCBP) must agree to use effective contraceptive methods from screening until at least:
• Cohort 1: 14 days after the surgical resection for subjects in Cohort 1
• Cohort 2:
• Nivolumab: 5 months after the last dose of either nivolumab or intralesional Flucelvax, whichever is later
• Pembrolizumab: 4 months after the last dose of either pembrolizumab or intralesional Flucelvax, whichever is later
• Ipilimumab: 3 months after the last dose of either ipilimumab or intralesional Flucelvax, whichever is later
• Relatlimab + nivolumab (marketed under the trade name Opdualag): 5 months after the last dose of either Opdualag or intralesional Flucelvax, whichever is later.
• Combination ipilimumab with other checkpoint inhibitor: Whichever is later:
• 3 months after the last dose of either ipilimumab or intralesional Flucelvax
• Above-bulleted recommendation for nivolumab or pembrolizumab
• Non-childbearing potential is defined as a woman who meets either of the following criteria: a) postmenopausal state defined as no menses for 12 months without an alternative medical cause, or b) documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy
• Effective contraception methods are defined as one of the following:
• True abstinence, defined as refraining from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject
• Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception
• Condoms and spermicide
• Diaphragm and spermicide
• Oral or implanted hormonal contraceptive
• An intra-uterine device
• WOCBP must have a negative pregnancy test (serum or urine)

Exclusion criteria

• Known allergy or intolerance to influenza vaccination
• Subjects with condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone/equivalent) or other immunosuppressive medications within 14 days of study drug administration
• Active, known or suspected autoimmune disease
• Active brain metastasis or leptomeningeal metastasis
• Diagnostic biopsy of ocular or mucosal melanoma
• Any melanoma therapy within 6 months of enrollment; though prior surgical resection is permitted
• Incarcerated patients
• Patients known to be HIV positive are eligible if they meet the following criteria within 30 days prior to randomization: stable and adequate CD4 counts (≥ 350 mm\^3), and serum HIV viral load of \< 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria
• Pregnant or lactating patients
• Patients incapable of independently providing consent