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J Clin Oncol. 2015 Jan 1;33(1):74-82. doi: 10.1200/JCO.2014.57.3329. Epub 2014 Nov 17.

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.

Author information

1
Kevin C. Conlon, 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 Sr, Cody J. Peer, and Thomas A. Waldmann, National Cancer Institute; Enrico Lugli, Hugh C. Welles, Michael C. Sneller, H. Clifford Lane, and Mario Roederer, National Institute of Allergy and Infectious Diseases, Bethesda; Jason L. Yovandich and Stephen P. Creekmore, National Cancer Institute, Frederick, MD; and Hugh C. Welles, Columbian College of Arts and Sciences, George Washington University, Washington, DC.
2
Kevin C. Conlon, 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 Sr, Cody J. Peer, and Thomas A. Waldmann, National Cancer Institute; Enrico Lugli, Hugh C. Welles, Michael C. Sneller, H. Clifford Lane, and Mario Roederer, National Institute of Allergy and Infectious Diseases, Bethesda; Jason L. Yovandich and Stephen P. Creekmore, National Cancer Institute, Frederick, MD; and Hugh C. Welles, Columbian College of Arts and Sciences, George Washington University, Washington, DC. tawald@helix.nih.gov.

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 coli-produced 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-limiting 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 γδ 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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01021059.

PMID:
25403209
PMCID:
PMC4268254
DOI:
10.1200/JCO.2014.57.3329
[Indexed for MEDLINE]
Free PMC Article

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