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IL-2 in Melanoma
Rethinking Cytokine Therapy in the Management of Advanced Melanoma

Released: February 15, 2021

Expiration: February 14, 2022

Elizabeth Buchbinder
Elizabeth Buchbinder, MD
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Although the treatment of melanoma has advanced by leaps and bounds with the advent of immune checkpoint inhibition and highly effective targeted therapies, substantial subsets of patients do not respond to these approaches or progress after an initial response. These patients have progressive, resistant disease for which there is a huge clinical need for additional therapies. In this commentary, I explore the use of cytokine therapy for patients with advanced melanoma who feel well enough to undergo additional treatment but whose disease is progressing on or resistant to their previous therapy. In particular, the use of high-dose interleukin (IL)-2 to stimulate the immune system in a meaningful, long‑term way may allow patients with resistant or refractory melanoma to achieve very durable responses.

Where Does Cytokine Therapy Fit in the Current Melanoma Treatment Landscape?
Most patients with melanoma receive immune checkpoint inhibitors (ICIs) and, if their tumor is BRAF mutated, BRAF/MEK inhibitor therapy. Cytokine therapy still has a role in melanoma for those patients who are resistant to or progress on these therapies. Although the response rate to cytokine therapy is low, the responses can be quite durable. My colleagues and I conducted retrospective analyses of IL‑2 therapy after ipilimumab and after PD‑1 inhibition in melanoma and renal cell carcinoma and identified a group of patients that not only responded to IL-2, but had durable responses. As such, a role remains for the clinically approved use of IL‑2. In addition, an opportunity exists to identify ways to better use these agents (ie, better target the IL‑2 and other cytokine receptors) in ways that facilitate long, durable responses. Ongoing research is looking at modifying IL‑2, to better target IL‑2 receptors so there is less negative regulation of the immune response. The goal of these approaches is to bring about more stimulation of activating T-cells and decreased stimulation of T regulatory cells. In addition, other cytokines (eg, interferon, IL-12) are being examined to see if there are better ways to use these drugs to stimulate the immune system, generate durable responses, and combine them with ICIs. Overall, ongoing research in melanoma is looking at novel ways to use cytokines to stimulate and activate the immune system while overcoming the toxicities and negative immune regulation that can occur with these drugs.

Patent Selection for IL-2 Therapy and Managing IL-2–Associated Toxicities
When ICIs and BRAF/MEK targeted therapies became available for melanoma, the use of IL-2 dropped quite a bit with the success of these other approaches. But for patients where these approaches failed additional therapy was required, and some received IL-2. The use of ICIs and IL-2 has led us to understand autoimmune toxicities much better, including what is going on in the body when the immune system gets overactivated and out of control. In addition, the use of CAR T-cells and other new immunotherapy approaches in cancers beyond melanoma can also cause overactivation of the immune system, including “cytokine storm”; there too, understanding how to counteract that (eg, with tocilizumab) helps to improve the treatment of patients. Understanding these dynamics and their management has helped improve management of adverse events from IL-2.

Although the ICI era has added to our understanding of the immune system, it has also resulted in new complications for giving IL‑2 safely and effectively in patients with melanoma. Physicians must carefully select which patients may be candidates for high‑dose IL‑2; in our clinic, IL-2 is one of the therapies we consider for patients when ICI therapy fails. Whether to use IL-2 often depends on the pattern of a patient’s disease. For instance, we do not use IL-2 in patients with melanoma and brain metastases. One major concern is the possible re-emergence of autoimmune toxicities from a prior line of therapy. This occurs rarely, but the risk represents a real challenge in safely treating these patients. Understanding a patient’s prior toxicities and ensuring that these have entirely resolved is important. It can be hard to differentiate these re-emergent ICI toxicities from IL‑2 toxicity itself; for example, if hepatitis re‑emerges, is it an autoimmune hepatitis or is it simply vascular redistribution and leakage that occurs with IL‑2? 

For patients who are on active steroids, we avoid immunotherapy and are more likely to choose targeted therapy, if indicated, or chemotherapy. Patients who have progressed on previous therapy with completely resolved toxicities are good candidates for IL-2, but this remains a very individual decision. Other factors to consider include the pattern of disease, the pattern of toxicity, other therapies under consideration, and available clinical trials of investigational therapies. Patients also need to be admitted in a timely manner for IL-2 therapy, and COVID-19 restrictions have complicated admitting patients. It is difficult to consider elective admissions at a time when hospitals do not have the capacity for those patients.

Looking Forward: IL-2 Combination Treatments and More
The idea of using cytokines to stimulate the system as a whole while continuing to “release the brakes” with checkpoint inhibition is really exciting. For example, an ongoing phase Ib/II study is investigating the combination of IL-2 plus the PD-1 inhibitor pembrolizumab in patients with unresectable or metastatic melanoma (estimated N = 65) (NCT02748564). Another very interesting novel approach is designed to turn immunologically “cold” tumors “hot” with injections of cytokines that can spur local inflammation, allowing for increased immune stimulation in combination with ICIs. In addition to local injection, packaging IL-2 or other cytokines into a virus or plasmid for targeted expression is another interesting approach. All of these approaches aim to better stimulate the immune system to target the cancer specifically without autoimmune toxicity.

I would strongly encourage physicians to refer their patients with resistant or progressive melanoma to centers equipped to give high-dose IL‑2. Many of these centers can also offer participation in clinical trials or have other therapies they would consider if a patient is not a candidate for high‑dose IL‑2. Of note, patients who have received PD‑1 or CTLA-4 inhibitors can benefit from high-dose IL‑2 and should be given that option. In other words, those referrals are really important.

Although high-dose IL-2 has been an approved option for melanoma for quite some time, in important ways, it is being reinvigorated as we understand more about immunotherapy and remains an important treatment option in our armamentarium. It will be really interesting and exciting going forward to see us learning how to use cytokines better and how to best integrate them into our evolving treatment regimens.

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