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

作者：Kevin C. Conlon, Enrico Lugli, Hugh C. Welles, Steven A. Rosenberg, Antonio Tito Fojo, John C. Morris, Thomas A. Fleisher, Sigrid Dubois, Liyanage P. Perera, Donn M. Stewart, Carolyn K. Goldman, Bonita R. Bryant, Jean M. Decker, Jing Chen, Tatyana Worthy, William D. Figg, Cody J. Peer, Michael C. Sneller, H. Clifford Lane, Jason L. Yovandich, Stephen P. Creekmore, Mario Roederer, Thomas A. Waldmann · 发表于：Journal of Clinical Oncology · 年份：2014 · DOI：10.1200/jco.2014.57.3329 · 被引用次数：717 · 研究领域：Immune Cell Function and Interaction、CAR-T cell therapy research、Lymphoma Diagnosis and Treatment

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...