Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer

Kevin C. Conlon, Enrico Lugli, Hugh C. Welles, Steven A. Rosenberg, Antonio Tito Fojo, John C. Morris, Thomas A. Fleisher, Sigrid P. Dubois, Liyanage P. Perera, Donn M. Stewart, Carolyn K. Goldman, Bonita R. Bryant, Jean M. Decker, Jing Chen, Tat'Yana A. Worthy, William D. Figg, Cody J. Peer, Michael C. Sneller, H. Clifford Lane, Jason L. YovandichStephen P. Creekmore, Mario Roederer, Thomas A. Waldmann

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods: We performed a first in-human trial of Escherichia coliproduced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results: Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-imiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients Conclusion: IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γ8 cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.

Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalJournal of Clinical Oncology
Volume33
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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