https://orcid.org/0000-0003-3290-9959
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ABSTRACT
Introduction
Mucosal melanomas are rare and aggressive forms of cancer that have consistently eluded meaningful recovery with various anticancer therapies. Patients with unresectable mucosal melanomas have benefited from prolonged survival with the use of systemic drugs, including immune checkpoint inhibitors, but prognosis for mucosal malignancies remains inferior compared to cutaneous melanomas. FDA breakthrough and orphan drug designations for novel IL-2 formulations bempegaldesleukin and nemvaleukin highlight the potential for restoring cytokine-based therapy as a viable option in treating mucosal melanomas.
Areas covered
In this review, we discuss the biological and clinical features of mucosal melanomas, the current therapies available to this patient population including anti-PD1 and targeted therapies, and the potential for integrating novel IL-2 formulations into the existing armamentarium. Recently published clinical trial outcomes evaluating IL-2-based drugs are critically evaluated within the context of the existing treatment landscape for mucosal melanomas.
Expert Opinion
We conclude that clinical trials are a key priority for eligible patients who may stand to benefit from IL-2 therapy. For patients with unresectable and advanced disease who are unable to participate in trials, anti-PD1 and targeted therapies may still be considered as front- and next-line treatments on a case-by-case basis.
Article highlights
Mucosal melanomas are rare and aggressive cancers associated with poorer prognoses than cutaneous melanomas. There remains a unmet need for effective systemic therapies to improve outcomes in metastatic and unresectable mucosal melanomas.
This article reviews the underlying biological mechanisms behind the immunogenic microenvironment of melanoma tumors and corresponding, novel immunotherapies, such as the cytokines and monoclonal antibodies.
Recombinant IL-2 (aldesleukin) was one of the first approaches in implementing cytokine therapy in treating melanomas. We describe the background of IL-2 use in melanoma and the high frequency of adverse events which restricted its widespread clinical adoption despite FDA approval.
Immune checkpoint inhibitors promote a T-cell-mediated antitumor immune response against tumor cells. Checkpoint inhibitors have improved progression free survival and overall survival across multiple clinical trials and have become the standard-of-care therapy for patients with malignant melanomas. Data from these human studies are concisely discussed within.
Finally, we highlight novel immunotherapy strategies under investigation targeting the IL-2 Receptor, which are formulated to promote an antitumor immune response by exploiting receptor binding kinetics while reducing toxicities. Ongoing clinical trials are evaluating the effectiveness of bempegaldesleukin and nemvaleukin in combination with checkpoint inhibitors, signaling the potential for a revival of IL-2-based therapies in the melanoma treatment landscape.
Abbreviations
| IL-2 | = | Interleukin 2 |
| TNM | = | Tumor, node, metastasis |
| RAF | = | Rapidly accelerated fibrosarcoma |
| CTLA-4 | = | Cytotoxic T-lymphocyte–associated antigen 4 |
| PD-L1 | = | Programmed death ligand 1 |
| PD-1 | = | Programmed death receptor 1 |
| APC | = | Antigen presenting cells |
| TILs | = | Tumor infiltrating lymphocytes |
| MDSC | = | Myeloid derived suppressor cells |
| Treg | = | Regulatory T cells |
| IFN-α-2b | = | Interferon-α2b |
| IL-2R | = | Interleukin 2 receptor |
| NK | = | Natural killer |
| PFS | = | Progression-free survival |
| ORR | = | Overall response rate |
| ICI | = | Immune checkpoint inhibitor |
| OS | = | Overall survival |
| TRAEs | = | Treatment related adverse events |
| Ipi | = | ipilimumab |
| Nivo | = | Nivolumab |
Declaration of interest
RD Carvajal has received consultancy fees from; Alkermes, Bristol Myers Squibb, Castle Biosciences, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics and Trisalus. He has served on the Clinical/Scientific Advisory Boards for Aura Biosciences, Chimeron and Rgenix, and received research funding to Columbia University from Amgen, Astellis, AstraZeneca, Bristol Myers Squibb, Corvus, Ideaya, Immunocore, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron and Roche/Genentech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.