Abstract
Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8(+) T cells, natural killer (NK) cells, and other cell types. We report final clinical and biological results of a phase II study of recombinant human IL-21 (rIL-21) in patients with metastatic melanoma. Open-label, single-arm, two-stage trial. unresectable metastatic melanoma, measurable disease by Response Evaluation Criteria in Solid Tumors, no prior systemic therapy (adjuvant IFN permitted), adequate major organ function, good performance status, no significant autoimmune disease, and life expectancy at least 4 months. antitumor efficacy (response rate). safety, blood biomarkers, and generation of anti-rIL-21 antibodies. rIL-21 (30 microg/kg/dose) was administered by intravenous bolus injection in 8-week cycles (5 dosing days followed by 9 days of rest for 6 weeks and then 2 weeks off treatment). Stage I of the study comprised 14 patients. One confirmed complete response (CR) was observed, and as per protocol, 10 more patients were accrued to stage II (total n = 24: 10 female and 14 male). Best tumor response included one confirmed CR and one confirmed partial response, both with lung metastases. Treatment was overall well tolerated. Biomarker analyses showed increases in serum soluble CD25, frequencies of CD25(+) NK and CD8(+) T cells, and mRNA for IFN-gamma, perforin, and granzyme B in CD8(+) T and NK cells. rIL-21 administered at 30 microg/kg/d in 5-day cycles every second week is biologically active and well tolerated in patients with metastatic melanoma. Confirmed responses, including one CR, were observed.
Highlights
Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8+ T cells, natural killer (NK) cells, and other cell types
We have previously reported our experience with recombinant human IL-21 (rIL-21) in a phase I trial of patients with metastatic melanoma (26 – 28) and another group has recently published the results of a trial in melanoma or renal cell carcinoma [29] using different treatment regimens
Materials and Methods rIL-21. rIL-21 was provided by Novo Nordisk. rIL-21 is expressed in Escherichia coli as the NH2-terminal methionylated form
Summary
Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8+ T cells, natural killer (NK) cells, and other cell types. This article reports our phase IIa study of IL-21 in patients with metastatic melanoma and builds on our phase I experience, showing that IL-21 is safe and well tolerated, induces relevant biological responses, and can lead to antitumor responses including a confirmed complete response. These results suggest that IL-21 may have a role as a single agent in the treatment of patients with melanoma. Preclinical studies showed that IL-21 has significant activity against various types of cancer in combination with monoclonal antibodies or signaling inhibitors Clinical trials of such combinations are currently ongoing and may indicate a role for IL-21in a variety of clinical indications. The IL-21 receptor is constitutively expressed at low levels on all lymphocyte subsets and on dendritic cells, with B cells having the highest constitutive expression
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