Clinical and Biological Efficacy of Recombinant Human Interleukin-21 in Patients with Stage IV Malignant Melanoma without Prior Treatment: A Phase IIa Trial

Abstract

Purpose: 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. Experimental Design: Open-label, single-arm, two-stage trial. Eligibility criteria: 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. Primary objective: antitumor efficacy (response rate). Secondary objectives: safety, blood biomarkers, and generation of anti-rIL-21 antibodies. rIL-21 (30 Ag/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). Results: 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 + Tcells, and mRNA for IFN-g, perforin, and granzyme B in CD8 + Tand NK cells. Conclusions: rIL-21administered at 30 Ag/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.

DNAM-1/CD155 Interactions Promote Cytokine and NK Cell-Mediated Suppression of Poorly Immunogenic Melanoma Metastases

“…When NK cells are adoptively transferred or activated in situ by cytokines, their clinical utility in selected malignancies, such as acute myeloid leukemia and malignant melanoma, is becoming apparent (3)(4)(5). Haploidentical NK cells can persist and expand in vivo and may have a role in the treatment of selected malignancies used alone or as an adjunct to hematopoietic stem cell transplantation (6).…”

Multiple Cytotoxic Factors Involved in IL-21 Enhanced Antitumor Function of CIK Cells Signaled through STAT-3 and STAT5b Pathways

“…Such qualities make IL-21 a suitable agent for immunotherapy especially in conditions such as HIV, Chronic Hepatitis renal cell carcinoma, melanoma and non hodgkin's lymphoma, where a sustained and potent immune response is necessary to keep pathogens at bay (Thompson et al, 2008;Davis et al, 2009;Yi et al, 2009;Yue et al, 2010;Timmerman et al, 2012). IL-21 like IL-15 is also unique among the common γchain family of cytokines in its ability to maintain CD8 T cell population without causing any activation induced cell death (Moroz et al, 2004).…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…Results from these trials have also shown the cytokine to be well tolerated with an increase in NK and CD8 C T cell function through increased IFNg and perforin production. 104,105 Despite these effects on CD8 C T and NK cells, IL-21 has been shown to inhibit DC activation and maturation and induces apoptosis of these cells via STAT3 signaling. 107,108 Thus IL-21 is detrimental toward DC function.…”