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Cancer Immunotherapy with Interleukin-2— Current Status and Future Developments

Oncology & Hematology Review, 2016;12(2): Epub ahead of print

Abstract:

High-dose interleukin-2 (HD IL-2) has been in clinical use in the treatment of metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) for over 20 years, and has produced substantial, durable responses in selected patients, resulting in cures in some patients with no ongoing therapy or chronic toxicity. However, use of the drug has remained limited owing to its significant acute toxicities, and the fact that only a minority of selected patients derive a response to treatment. Recent registry data support the use of HD IL-2 as first-line therapy in mRCC and mM, producing major responses for some and thus reducing the requirement for long-term therapy. In addition, an enhanced understanding of the role of IL-2 has led to the development of new therapeutic approaches to maximize the anti-tumor response of IL-2. These strategies include combined treatment with vaccines, antibody treatments to block inhibitory pathways, or adoptive cell transfer of T cells. These data and new approaches have led to continued use of HD IL-2 and may increase the number of patients who derive benefit from this treatment.
Keywords: Interleukin-2, immunotherapy, renal cell carcinoma, melanoma
Disclosure: Shilpa Gupta has participated in Advisory Boards and speakers’ bureau for Genentech. Neeraj Agarwal has participated in Advisory Board for Pfizer, Exelixis, Cerulean, Argo and received research funding from Pfizer. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Acknowledgments: Editorial assistance was provided by Katrina Mountfort at Touch Medical Media, funded by Prometheus.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
Received: March 07, 2016 Accepted: April 13, 2016
Correspondence: Shilpa Gupta, Division of Hematology, Oncology and Transplantation, 420 Delaware, SE, MMC 480, Minneapolis, MN 55455, US. E: guptash@umn.edu
Support: The publication of this article was supported by Prometheus. The views and opinions expressed are those of the authors and do not necessarily reflect those of Prometheus. The authors provided Prometheus with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion.

Interleukin 2 (IL-2, Proleukin® Prometheus Laboratories Inc., San Diego, US.) is a recombinant protein that plays an essential role in the development and function of a spectrum of T cells, including regulatory T cells, a naturally occurring population of CD4+ T cells that are vital to the control of inflammatory responses.1 Consequently, IL-2 has numerous antitumor effects, including stimulating T-cell proliferation and function; augmenting natural killer cell proliferation and cytotoxic activity; and triggering the release by activated lymphocytes of cytokines, such as interferon gamma, and tumor necrosis factor (see Figure 1).2

IL-2 was approved by the US Food and Drug Administration (FDA) in 1992 for the treatment of metastatic renal cell carcinoma (mRCC) and was approved for metastatic melanoma (mM) in 1998, after clinical trials demonstrated that it was capable of inducting complete responses (CRs) in a minority of patients.3,4 Following its approval for mRCC, a subsequent clinical trial investigated the use of lower-dose regimens but concluded that superior outcomes were observed with high-dose (HD) IL-2.5 Since then, HD IL-2 has remained one of the few treatments for mRCC and mM with the ability to produce CRs that are durable for decades without further therapy. The administration of HD IL-2 is associated with mainly acute short-term toxicities. One of its most significant toxicities is capillary leak syndrome with effects on multiple organ systems. This results in hypotension and reduced organ perfusion that can be severe but is manageable and reverses upon completion of therapy. The administration of HD IL-2 requires hospitalization with intensive monitoring, in specialized centers with personnel who are experienced in the management of this regimen and its side effects. Thus, not all oncology practices have developed an IL-2 therapy program and referrals to specialized centers have limited the utilization.

The introduction of oral targeted therapies for mRCC has shifted attention from HD IL-2. In the last decade, several targeted therapies have been approved for mRCC, including sorafenib, sunitinib, bevacizumab, pazopanib, axitinib, everolimus, and temsirolimus.6Recently, the tyrosine kinase inhibitor (TKI) cabozantinib has been approved by the FDA following phase III study data that demonstrated improved progression-free survival (PFS), objective response rates, and overall survival (OS) in the second line setting compared with everolimus, in a phase III trial. 7,8 This agent targets MET and KIT in addition to the VEGF receptor. More recently, lenvatinib, an oral TKI of vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor (FGF) receptors 1–4, platelet-derived growth factor receptor α (PDGFRα), RET, and KIT, was approved after it showed improved objective responses, PFS, and OS in combination with everolimus, compared to everolimus alone in a in a randomized study.9 As with other targeted therapy, chronic toxicities requiring dose reductions were observed with both cabozanatinib and lenvatinib. These therapies require long-term administration, rarely result in CRs, and are associated with the eventual development of resistance. Moreover, the targeted agents result in significant chronic toxicities that need to be prevented and/or managed aggressively throughout ongoing treatment.

Although the use of HD IL-2 has diminished following the introduction of targeted therapies, a recent study (n=2,351) has found a slight increase in use of HD IL-2 in the years 2004 to 2012, possibly reflecting the fact that targeted therapies do not induce CRs and require continuous drug administration.10 In the recent HD aldesleukin ‘select’ trial, in patients with mRCC, 11% of patients remained progression free at 3 years and the median OS was 42.8 months.11 This was achieved utilizing limited drug exposure—2 to 4 weeks in total. The objective response rate of all patients (n=120) to HD IL-2, confirmed by independent review, was 25% (95% confidence interval [CI], 17.5 to 33.7%).12

Recently, a large retrospective study of patients with mRCC treated with HD IL-2 was published. Of 391 patients with mRCC, the best responses on treatment with HD IL-2 were as follows: complete response (CR; 9%), partial response (PR; 10%), stable disease (32%), progressive disease (42%), not evaluable for response (7%). Notably, there were no significant differences in PFS (hazard ratio [HR] 0.74, 95% CI 0.48 -1.1, p=0.14) or OS (HR 0.66, 95% CI 0.39-1.09, p=0.11) between patients achieving PR versus stable disease. However, there were significant differences in PFS (HR 0.13, 95% CI 0.09-0.22, p<0.0001) and OS (HR 0.33, 95% CI 0.23-0.48, p<0.0001) between patients achieving stable disease compared to those with progressive disease and who were not evaluable. In conclusion, a meaningful survival benefit with HD IL-2 was achieved in ~50% mRCC patients and extended beyond to those achieving complete or PR, i.e., to those patients who only achieved stale disease as the best response.12

In very recent years, the programmed death-1 (PD-1) pathway, a regulator of tumor-induced immune suppression, has become therapeutic target in solid tumors. Nivolimumab, a checkpoint inhibitor of binding of PD-1 with its ligands, received FDA approval for mRCC as second-line therapy,13 following a randomized, open-label phase III study (n=821) in which patients with advanced RCC who had received previous treatment were randomized to nivolimumab or everolimus. The OS was longer for the nivolumab group versus the everolimus group, 23.6 months versus 19.8 months respectively and fewer grade 3 or 4 adverse events occurred with nivolumab compared with everolimus.14 However, the CR rate for nivolumab was only 1% and <1% in the everolimus group. In addition, in a phase I study (n=34) nivolimumab demonstrated objective responses that in some patients persisted after drug discontinuation.15 While these responses are promising, treatment with nivolimumab currently requires long-term drug administration and patients do experience side effects such as fatigue, rash, pruritis, nausea, and diarrhea. The durability of response continues to be evaluated.

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Keywords: Interleukin-2, immunotherapy, renal cell carcinoma, melanoma