CITN11-02 phase I trial of subcutaneous recombinant human IL-15 (rhIL-15) is associated with expansion of circulating CD56+ NK cells and CD8+ T cells

Abstract

Abstract Background IL-15 is a high priority for clinical development because of its homeostatic effects on both NK cells and CD8+ T cells, and minimal effect on regulatory T cells. The Cancer Immunotherapy Trials Network is conducting a phase I dose-escalation study of subcutaneous (SQ) rhIL-15 in advanced melanoma, renal cell, non-small cell lung and squamous cell head and neck carcinoma patients. Methods A cycle consists of 5 daily SQ injections of rhIL-15 (E.coli-derived, NCI) given Monday-Friday for two weeks, then 2 weeks observation. The absolute lymphocyte count is tested every injection day, and whole blood flow cytometric analyses are conducted on Days 1, 11 and 15 of each cycle. Results Three patients each were treated at the 0.25, 0.5, 1.0 and 3.0 mcg/kg dose levels and six patients at 2.0 mcg/kg/dose (N=18). Seventeen patients completed ≥1 cycle, with one dose limiting toxicity (DLT) at 3.0 mcg/kg and one serious adverse event at 2.0 mcg/kg. Flow cytometric data indicate a consistent increase in the frequency of CD56+CD3− NK cell frequencies peaking at Day 15 of Cycle 1 (Day 12=last dose), with lesser increases in subsequent cycles. The median fold-increase in circulating NK cells during Cycle 1 demonstrated dose responsiveness and peaked at 11.5-fold with 3.0 mcg/kg. By contrast, the maximum fold-increase in circulating CD8+ T cells was 2.6-fold. Conclusion SQ rhIL-15 has been well tolerated and the 3.0 mcg/kg dose cohort is being expanded. Higher doses of rhIL-15 were associated with profound increases in circulating NK cells with significant but smaller increases in CD8+ T cells. Outpatient use of SQ rhIL-15 is safe and will be combined with other cancer immunotherapies. Study support: NIH 1U01 CA154967-01 (Clinical Trials.gov NCT01727076).