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Interleukin 2 and experimental immunotherapy approaches for advanced melanoma

Interleukin 2 and experimental immunotherapy approaches for advanced melanoma
Literature review current through: Jan 2024.
This topic last updated: Dec 07, 2023.

INTRODUCTION — An improved understanding of the immune system and its activation has led to the development of immune checkpoint inhibitors and targeted therapies, which are routinely incorporated into the treatment of advanced and metastatic melanoma.

High-dose interleukin 2 (IL-2) was the first immunotherapy approach to produce durable remissions in patients with advanced disease. However, these benefits were limited to a small fraction of patients, and treatment was associated with substantial toxicity.

The use of high-dose IL-2 in melanoma has largely been replaced with immune checkpoint inhibitors directed against programmed death 1 protein (PD-1) alone or in combination with antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). In addition, targeted therapy directed against the mitogen-activated protein (MAP) kinase pathway has provided an additional important treatment option for patients with advanced disease and a V600 mutation of BRAF.

The results with high-dose IL-2 and the potential role of other experimental immunotherapy approaches are reviewed here. The principles of cancer immunotherapy, toxicities associated with immune checkpoint inhibitors, and the treatment of melanoma are discussed separately:

(See "Principles of cancer immunotherapy".)

(See "Toxicities associated with immune checkpoint inhibitors".)

(See "Overview of the management of advanced cutaneous melanoma".)

(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

(See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

(See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

(See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

INTERLEUKIN 2 — IL-2 was initially identified as a T-cell growth factor in the 1970s. Recombinant IL-2 subsequently was shown to have potent, dose-dependent immunomodulatory and antitumor activity in a number of murine tumor models [1]. These observations led to the development of high-dose IL-2 regimens for use in patients with metastatic melanoma.

Efficacy — Initial clinical studies used high-dose bolus recombinant IL-2 (600,000 to 720,000 international units/kg intravenously every eight hours on days 1 to 5 and 15 to 19, with a maximum of 28 doses per course) either alone or in combination with lymphokine-activated killer (LAK) cells.

Extended follow-up of 270 patients treated with high-dose IL-2 at the National Cancer Institute and the Cytokine Working Group institutions demonstrated that this approach had a clinically significant benefit in a minority of patients [2-4]. The objective response rate was 16 percent, with a median duration of nine months (range 4 to 106+ months), and 59 percent of complete responders remained progression free at seven years. At a minimum follow-up of six years, 44 percent of all responders remained alive, the vast majority disease or progression free. In addition, no patient responding for longer than 30 months had progressed, suggesting that some patients were "cured."

Toxicity — The severe multiorgan toxicity associated with high-dose IL-2 treatment limited its use to patients with excellent organ function who were treated by experienced clinicians in specialized programs capable of providing the necessary intensive care.

Serious side effects include hypotension, cardiac arrhythmias, pulmonary edema, fever and chills, metabolic acidosis, nausea and vomiting, dyspnea and peripheral edema due to increased capillary permeability, neurotoxicity, oliguria and impaired renal function, rash, and rarely, death. Bacterial infection, particularly catheter-related sepsis, contributes significantly to the toxicity of IL-2 [3]. Antibiotic prophylaxis greatly reduced the incidence of catheter-related sepsis and dramatically improved the safety of this therapy.

Alternative interleukin 2 regimens — Multiple approaches have been studied in an attempt to improve the durable response rate and/or minimize toxicity. In addition to alternative dosing schedules, these include combining IL-2 with activated peripheral blood lymphocytes (LAK cells) [5], interferon alpha, peptide vaccines [6], chemotherapy (biochemotherapy) [7,8], and various toxicity reduction agents, such as tumor necrosis factor receptor (TNFR) and interleukin 1 receptor (IL-1R) antagonists. Although activity was seen with all of these approaches, none of these approaches resulted in a sufficient improvement in the therapeutic index to have them adopted as an alternative treatment regimen.

Studies have focused on modified IL-2 agents that are designed to preferentially activate CD8+ and natural killer (NK) cells, such as bempegaldesleukin [9]. Although initial studies suggested clinical efficacy for the addition of bempegaldesleukin to nivolumab [10], a randomized trial failed to demonstrate an improvement in overall survival with this strategy (24 month overall survival rate of 55 percent in both groups) [11]. However, grade 3 to 4 treatment-related adverse events were higher in the bempegaldesleukin and nivolumab group compared with nivolumab alone (22 versus 10 percent).

Interleukin 2 plus tumor-infiltrating lymphocytes — High-dose IL-2 has also been studied with autologous tumor-infiltrating lymphocytes (TILs) [12]. Ongoing research approaches include the use of gene-modified TILs and neoantigen-targeted TILs. IL-2 has been used in conjunction with TILs and nonmyeloablative lymphodepletion chemotherapy regimens [13-16]. This approach is highly effective in patients with immunotherapy-refractory melanoma [17,18]. Further details are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'What is the role of tumor-infiltrating lymphocytes?'.)

GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR — In vitro granulocyte-macrophage colony-stimulating factor (GM-CSF) activates macrophages to become cytotoxic for human melanoma cells [19], and it mediates the proliferation, maturation, and migration of dendritic cells, which play an important role in the induction of T-cell-mediated immune responses [20].

A cooperative group phase III trial (Eastern Cooperative Oncology Group [ECOG] 4697) did not demonstrate an improvement in overall survival with GM-CSF compared with placebo or a peptide vaccine [21]. However, in a randomized phase II trial, GM-CSF plus ipilimumab improved overall survival and decreased toxicity compared with ipilimumab alone [22]. This approach remains investigational and further studies are necessary. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Investigational agents'.)

INTERFERON ALPHA — Immunotherapy with interferon alpha (IFNa) is no longer used for the treatment of advanced disease, and the development of immune checkpoint inhibitors has effectively replaced this agent.

IFNa was the first recombinant cytokine used to treat metastatic melanoma [23,24]. However, the usefulness of IFNa for patients with metastatic melanoma was limited, since tumor responses were largely confined to patients with small volumes of cutaneous or soft tissue disease, and the median duration of response was only approximately four months [25]. Access to IFNa-2b is also limited as the manufacturer has discontinued production.

VACCINES — A number of vaccine approaches have been studied to stimulate an immune response against melanoma. These have included vaccines targeting T-cell antigens, gangliosides, and whole-cell or cell lysates. However, none of these approaches has proven clinically useful.

Newer vaccine approaches are focusing on melanoma neoantigen-specific T-cells. (See "Principles of cancer immunotherapy", section on 'Vaccines'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Interleukin-2 – Treatment with high-dose bolus interleukin 2 (IL-2) was the first effective systemic immunotherapy for the treatment of advanced melanoma. IL-2 treatment is associated with prolonged survival in a minority of carefully selected patients and may actually result in cure.

However, IL-2 treatment is associated with severe and potentially life-threatening cardiovascular, respiratory, and infectious complications, and its use has been replaced by the development of more effective and less toxic immune checkpoint inhibitors. (See 'Interleukin 2' above and "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

Interferon alpha – Interferon alpha (IFNa) is no longer used for the treatment of advanced disease, and the development of immune checkpoint inhibitors has effectively replaced this agent. (See 'Interferon alpha' above.)

Other agents – Other immunotherapy agents under investigation include vaccines and granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with immune checkpoint inhibitors. (See 'Granulocyte-macrophage colony-stimulating factor' above and 'Vaccines' above.)

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