Therapeutic Role and Toxicity Profile of High-Dose Interleukin-2 in Metastatic Melanoma and Renal Cell Carcinoma: A Narrative Review

Background: High-dose interleukin-2 (HD IL-2) is one of the earliest clinically proven immunotherapy approaches for solid tumors. In a select subset of patients with stage III or IV metastatic melanoma and renal cell carcinoma, HD IL-2 has demonstrated the ability to induce significant and long-lasting therapeutic benefits, including durable remissions achieved without the need for further systemic treatment. Biological Rationale: For HD IL-2 to produce durable therapeutic benefit, it must elicit a robust immune response through marked proliferation and functional activation of immune effector cells, particularly cytotoxic T lymphocytes and natural killer cells. These immune mechanisms underpin the immune-mediated tumor regression observed in responsive patients. Clinical Efficacy: Experience from early National Cancer Institute clinical trials, as well as subsequent multi-institutional and registry-based studies, has established objective response rates of approximately 15–20% in metastatic melanoma and 20–25% in metastatic renal cell carcinoma. A small but clinically significant minority of patients achieved durable complete remissions. Those attaining complete responses have demonstrated prolonged progression-free and overall survival extending many years beyond completion of HD IL-2 therapy, often without additional treatment. Toxicity and Limitations: The clinical use of HD IL-2 is constrained by its narrow therapeutic window and significant toxicity profile. Major adverse effects include capillary leak syndrome, cardiovascular instability, renal impairment, and neuropsychiatric toxicity. These risks necessitate inpatient administration, intensive monitoring, and restriction of therapy to highly specialized centers with appropriate expertise. Conclusion: This narrative review evaluates the biological rationale, therapeutic efficacy, toxicity profile, and current clinical relevance of HD IL-2. Its role is contextualized within contemporary treatment paradigms dominated by immune checkpoint inhibitors and emerging engineered IL-2 variants, highlighting HD IL-2’s enduring significance as a therapy capable of inducing durable, treatment-free remissions in carefully selected patients. Keywords: High-dose interleukin-2; Immunotherapy; Metastatic melanoma; Renal cell carcinoma; Cytokine therapy; Immune-mediated tumor response; Capillary leak syndrome; Durable remission; Immune checkpoint inhibitors; Engineered IL-2 variants.