Update on use of aldesleukin for treatment of high-risk metastatic melanoma

Abstract

High-dose interleukin-2 has been used for the treatment of metastatic melanoma since 1998 based on data proving durable complete responses in up to 10% of treated patients. The immunomodulatory effects of this critical cytokine have been instrumental in the development of immunotherapy for melanoma and other cancers. However, with the advent of new therapies, its use as a front-line agent has come into question. Nonetheless, there is still a role for interleukin-2 as monotherapy, as well as in combination with other agents and in clinical trials. In this article, we review preclinical and clinical data regarding interleukin-2, its pharmacology and mechanism of action, its toxicity profile, and its use in ongoing and planned clinical trials. We also explore the future of this agent within the treatment landscape for melanoma.

Keywords: aldesleukin; immunotherapy; melanoma.

Figure 1

IL-2R signaling triggers three distinct pathways. The IL-2R is comprised of three subunits that may be assembled in three different combinations (top left). The low affinity form contains only CD25 (IL-2Rα), the intermediate affinity form contains subunits CD122 and CD132 (IL-2Rβ and IL-2Rγ), and the high affinity form contains subunits CD25, CD122, and CD132. Importantly, signaling occurs through the CD122 and CD132 subunits. Upon binding to IL-2, the IL-2R recruits JAK1 and JAK3, which cause downstream signaling through the STAT5, phosphatidylinositol-4 5-bisphosphate 3-kinase, or mitogen-activated protein kinase pathways and result in expression of the FoxP3 transcription factor, or proliferation signals. Abbreviations: IL-2, interleukin-2; IL-2R, interleukin-2 receptor.

Figure 2

IL-2 therapy promotes both immune activation and immune suppression in melanoma tumors. The tumor microenvironment is highly immunosuppressive and can contain limited amounts of infiltrating T lymphocytes (left). Upon treatment with IL-2 (right), effector T-cells are expanded and recruited into tumors, along with regulatory T-cells that bind IL-2 more efficiently and thus deplete it from the microenvironment. IL-2 also results in activation of monocytes and increases in production of interferon-gamma, which may result in increased antigen presentation and recognition of tumor cells by infiltrating T-cells. Finally, IL-2 causes increases in granzymes A, B, and C, as well as in perforin, which allow for better cytotoxicity against tumor cells upon recognition by antigen-specific T-cells. IL-2 therapy has also been shown to be associated with increased vascular leakage, a side effect linked to both efficacy and toxicity of IL-2 therapy. Abbreviations: IL-2, interleukin-2; MHC, major histocompatibility complex.

Figure 3

First-line therapy options for patients with metastatic melanoma. The treatment algorithm is stratified by BRAF mutation analysis result, patient performance status, and disease burden. Abbreviations: CNS, central nervous system; IL-2, interleukin-2; PS, performance status.