An Open-Label, Two-Arm, Phase I Trial of Recombinant Human Interleukin-21 in Patients with Metastatic Melanoma

Abstract

Purpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8 + T cells and natural killer cells.We report a phase 1study of recombinant human IL-21in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors. Experimental Design: Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 Ag/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9). Results: Twenty-nine patients entered the study. IL-21was generally well tolerated and no DLTs were observed at the 1, 3, and 10 Ag/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 Ag/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8 + cells. One partial tumor response observed after treatment with IL-21 for 2 Â 6 weeks (3/wk) became complete 3 months later. Conclusions: IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 Ag/kg in the 5+9 regimen.

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

“…In the current study, we administered IL-21, a potent immunomodulatory cytokine, to ART-treated, (16). Last, IL-21 is currently being evaluated in several phase I and II cancer clinical trials, with limited toxicity and encouraging single-agent activity (17,(47)(48)(49). Importantly, a historic limitation of the SIV/RM model for studies of HIV residual disease, i.e., the lack of an optimized ART that fully suppresses virus replication, has been recently overcome, with a number of studies showing that the combination of tenofovir, emtricitabine, an integrase inhibitor (raltegravir or dolutegravir), and darunavir can durably suppress SIV infection of RMs to clinically relevant levels (50-53).…”

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

“…An assessment of DNAM-1 ligand (CD155) and other ligand (CD70, CD80, MICA/B) status and lung metastases response to IL-2 in patients beckons. IL-21 has been examined clinically in phase I trials in patients with malignant melanoma and renal cell carcinoma and has a superior safety profile compared with IL-2 (49,50). Although IL-21 has now entered various phase II trials (5), the importance of DNAM-1 and their tumor ligands in the NK cell effector function and antitumor activity of this cytokine in humans remains unknown.…”

Interleukin-21 can efficiently restore impaired antibody-dependent cell-mediated cytotoxicity in patients with oesophageal squamous cell carcinoma

“…A phase I study involving IL-21 monotherapy for metastatic melanoma or renal cell carcinoma reported that monotherapy was well tolerated and exhibited anti-tumour activity in some patients (Davis et al, 2007;Thompson et al, 2008), thereby suggesting that IL-21 may have an anti-tumour effect as a monotherapy. However, this study clearly showed that IL-21 could efficiently enhance impaired ADCC activity in ESCC patients, suggesting that combination therapy of Trastuzumab or Cetuximab with IL-21 might result in the enhancement of the anti-tumour effect.…”