Interleukins in the Treatment of Melanoma

Melanoma, a highly aggressive form of skin cancer, has witnessed transformative advancements in therapeutic strategies over the past two decades. While traditional approaches such as surgical resection, chemotherapy, and targeted therapies like BRAF/MEK inhibitors have improved clinical outcomes, immunotherapy has emerged as a cornerstone in melanoma management. Among immunotherapeutic agents, interleukins (ILs)—a family of cytokines mediating communication between immune and non-immune cells—have gained attention for their dual role in modulating tumorigenesis and antitumor immunity. This article explores the therapeutic potential of IL-2, IL-15, IL-10, and IL-18 in melanoma, focusing on recent innovations in cytokine engineering, combination strategies, and clinical trial outcomes.

IL-2: Balancing Efficacy and Toxicity

IL-2, a pleiotropic cytokine, stimulates the proliferation and activation of CD8+ T cells, natural killer (NK) cells, and CD4+ T helper subsets while suppressing regulatory T cells (Tregs). Its receptor comprises three subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and IL-γ (CD132). High-dose IL-2 therapy, FDA-approved for metastatic melanoma since 1998, achieves durable complete responses (CRs) in 5–10% of patients. However, severe toxicity—including capillary leak syndrome and multi-organ dysfunction—limits its clinical utility. To address these challenges, engineered IL-2 variants with modified receptor affinities have been developed.

NKTR-214 (Bempegaldesleukin), a PEGylated IL-2 analog, preferentially binds the intermediate-affinity IL-2Rβγ complex, favoring CD8+ T and NK cell expansion over Treg activation. Preclinical studies demonstrated enhanced tumor infiltration of effector lymphocytes and synergy with anti-CTLA-4 antibodies. In a phase I trial (NCT02869295), NKTR-214 monotherapy induced partial responses (PRs) in 2/7 melanoma patients and stable disease (SD) in 4/7. Subsequent combination with nivolumab (anti-PD-1) in 41 advanced melanoma patients (NCT02983045) yielded an objective response rate (ORR) of 52.6% and CR rate of 34.2%, with manageable toxicity. A phase III trial (NCT03635983) comparing NKTR-214 plus nivolumab versus nivolumab alone is ongoing.

ALKS 4230, another IL-2 variant, integrates a circularly permuted IL-2 structure fused to IL-2Rα’s extracellular domain. This design selectively activates CD122+ effector lymphocytes while sparing Tregs. Preclinically, ALKS 4230 outperformed native IL-2 in expanding NK cells and reducing Treg proliferation. A phase II trial (NCT04830124) is evaluating its efficacy in anti-PD-1-refractory melanoma.

NARA1leukin, a fusion of IL-2 and the anti-IL-2 monoclonal antibody NARA1, masks the CD25-binding site, abolishing Treg activation. In murine models, it induced robust CD8+ T cell expansion and suppressed melanoma metastasis more effectively than IL-2/NARA1 complexes. These advances highlight the potential of structural engineering to enhance IL-2’s therapeutic index.

IL-15: Expanding Antitumor Lymphocytes

IL-15 shares functional overlap with IL-2, promoting CD8+ T cell and NK cell activation without stimulating Tregs. Its receptor consists of IL-15Rα and the shared IL-2Rβγ complex. Despite promising preclinical antitumor activity, early clinical trials of recombinant human IL-15 (rhIL-15) showed limited efficacy.

ALT-803 (N-803), an IL-15 superagonist complex, combines an IL-15 mutant (N72D) with IL-15Rα-Fc to enhance receptor binding and prolong half-life. In a phase I trial (NCT01946789), ALT-803 monotherapy in 24 solid tumor patients (9 melanoma) induced NK and CD8+ T cell proliferation but no objective responses. However, combination with nivolumab in a phase Ib trial (NCT02523469) achieved a 29% ORR in refractory non-small cell lung cancer, suggesting potential for melanoma applications. A phase II trial (NCT03228667) is evaluating ALT-803 with anti-PD-1/PD-L1 agents.

NIZ985, a heterodimeric IL-15/IL-15Rα complex, demonstrated early promise in a phase I trial (NCT04261439). As a monotherapy, it stabilized disease in a patient with spindle cell ocular melanoma. Combined with spartalizumab (anti-PD-1), it elicited PRs in 1/8 cutaneous melanoma patients and SD in 3/8.

BJ-001, a tumor-targeted IL-15 fusion protein, incorporates an integrin-binding motif to localize cytokine activity to the tumor microenvironment (TME). Early-phase data (NCT04294576) indicate dose-dependent NK cell expansion without Treg modulation, supporting further evaluation in combination regimens.

IL-10: Dual Roles in Immune Regulation

IL-10, traditionally viewed as immunosuppressive, exhibits context-dependent antitumor effects. High-dose IL-10 activates tumor-specific CD8+ T cells while dampening pro-tumoral inflammation.

Pegilodecakin (AM0010), PEGylated IL-10, demonstrated single-agent activity in a phase I trial (NCT02009449), with 1/4 melanoma patients achieving a PR. In combination with pembrolizumab or nivolumab (NCT02009449), pegilodecakin increased Th1/Th2 polarization and expanded PD-1+ CD8+ T cells. Among 37 melanoma patients, the combination yielded SD in 3/37, highlighting modest efficacy compared to renal cell carcinoma (40% ORR) and NSCLC (43% ORR).

IL-18: Overcoming Decoy Receptor Resistance

IL-18 stimulates NK cells and effector T cells via IL-18R1 but is neutralized by IL-18-binding protein (IL-18BP), a decoy receptor. Early trials of recombinant IL-18 (NCT00107718) showed limited efficacy (1 PR in 64 melanoma patients), prompting engineering of decoy-resistant variants.

DR-18 (ST-067), an IL-18 mutant resistant to IL-18BP, enhances NK cell cytotoxicity and reverses PD-1 resistance in MHC-I-negative tumors. Preclinical studies in B16-F10 models demonstrated DR-18’s ability to reduce exhausted T cell populations and augment CAR-T cell efficacy. A phase Ia/II trial (NCT04787042) is evaluating DR-18’s safety and efficacy in advanced solid tumors, including melanoma.

Synergistic Strategies and Future Directions

Combining ILs with immune checkpoint inhibitors (ICIs) or adoptive cell therapy (ACT) represents a promising frontier. For instance:

• NKTR-214 + Nivolumab: Synergistic CD8+ T cell activation and TME remodeling.
• ALT-803 + Anti-PD-1: Reinvigoration of ICI-refractory tumors via NK cell engagement.
• IL-18-Secreting CAR-T Cells: Enhanced persistence and intratumor activity in murine models.

Challenges remain, including cytokine-related toxicity, tumor heterogeneity, and immune evasion mechanisms. Computational approaches, such as neoleukin-2/15 (Neo-2/15), a de novo IL-2/15 mimic, exemplify innovative strategies to bypass receptor limitations. Neo-2/15’s stability and lack of immunogenicity in preclinical models underscore the potential of synthetic biology in cytokine design.

Conclusion

Interleukins occupy a critical niche in melanoma immunotherapy, bridging innate and adaptive immunity. While monotherapies have shown limited efficacy, engineered variants and rational combinations with ICIs, ACT, or targeted therapies hold transformative potential. Clinical trials underway, such as NKTR-214/nivolumab and ALT-803/anti-PD-1, aim to validate these approaches. Future research must address pharmacokinetic optimization, biomarker discovery, and patient stratification to maximize therapeutic benefits. As cytokine engineering and synthetic biology advance, IL-based therapies are poised to redefine melanoma treatment paradigms.

doi.org/10.1097/CM9.0000000000001929

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