Table 1. FDA-approved melanoma immunotherapies.

Strategy	Agent	Class	Mechanism of Action	Year of FDA approval	Monotherapy vs. Adjuvant	Target Patient Population	Route(s)/ Regimen(s)	Predictors of Favorable Response Rates	Notable Adverse Drug Reactions (ADRs)
Non-specific stimulation of immune system effector cells	Interferon-alpha (IFN-α)	Cytokine Protein	Directly inhibits tumor cell proliferation. Enhances innate & adaptive immunity. Facilitates tumor antigen recognition via enhanced MHC I receptor expression. Represses oncogenes and induces tumor suppressor gene expression. Inhibits angiogenesis.	1995 (IFN-α) 2011 (pegylated IFN-α2b)	Adjuvant	Stage II-III resected melanoma patients with good performance status and no evidence of psychiatric or autoimmune disease	20 MU/m2 IV daily × 1 mo, followed by 10 MU/m2 SC TIW × 1 yr	IFN-α: micrometastatic disease peg-IFNα: ulcerated primary lesions, micrometastatic disease	Hepatotoxicity
	High-Dose Interleukin 2 (HD IL-2), Aldesleukin	Cytokine Protein	Activates B, T, & NK cells, facilitating cytolytic destruction of tumor cells	1998	1st-line monotherapy	Intravenous: stage IV BRAF wild-type melanoma patients with good performance status and no evidence of CNS disease Intralesional injections: inoperable in-transit metastases	Intravenous: 600–720k IU/kg q8h × 14 consecutive doses over 5 d, repeat w/in 6–9 d Intralesional: 0.3–18 mm IU each lesion SC 2-5x/wk	NRAS mutations, limited SC or cutaneous metastatic disease, absence of elevated serum LDH, VEGF, fibronectin, and CRP	Hypotension, pulmonary and systemic edema, renal insufficiency Intralesional injections minimize systemic toxicity
Modulation of immune system checkpoints with monoclonal antibodies (mAbs)	Ipilimumab	Anti-CTLA-4 mAb	Blocks CTLA-4 receptor on tumor cells, thereby circumventing downregulation of the T cell response	2011	Monotherapy in unresectable and/or metastatic disease Adjuvant therapy in resectable disease at high risk of recurrence		10 mg/kg IV q3W × 4 doses, then q12W maintenance	Baseline high tumor cell expression of FOXP3 and indolamine 2,3 dioxygenase (IDO) as well as high tumor infiltrating lymphocyte count	GI toxicity including colitis, hepatotoxicity, nephrotoxicity, thyroid toxicity
	Nivolumab	Anti-PD-1 mAb	Blocks PD-1 receptor on immune effector cells, circumventing downregulation of the cellular immune response	2014	2nd-line monotherapy	Metastatic melanoma, refractory to CTLA-4 and/or BRAF inhibition	3 mg/kg IV q2W	Higher PDL-1 expression on tumor cells	Colitis, hepatoxicity, pulmonary toxicity, nephrotoxicity, thyroid toxicity
	Pembrolizumab (MK-3475)	Anti-PD-1 mAb	Blocks PD-1 receptor on immune effector cells, circumventing downregulation of the cellular immune response	2014	2nd-line monotherapy	Metastatic melanoma patients post-treatment with ipilimumab or combination ipilimumab and BRAF inhibition in those with BRAF-mutated tumors	2 mg/kg IV q3W	Higher PDL-1 expression on tumor cells	Cellulitis, sepsis, renal failure, pneumonia, GI toxicity, anemia