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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
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.
Kevin C
KC
Conlon
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.
Enrico
E
Lugli
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.
Hugh C
HC
Welles
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.
Steven A
SA
Rosenberg
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.
Antonio Tito
AT
Fojo
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.
John C
JC
Morris
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.
Thomas A
TA
Fleisher
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.
Sigrid P
SP
Dubois
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.
Liyanage P
LP
Perera
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.
Donn M
DM
Stewart
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.
Carolyn K
CK
Goldman
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.
Bonita R
BR
Bryant
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.
Jean M
JM
Decker
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.
Jing
J
Chen
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.
Tat'Yana A
TA
Worthy
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.
William D
WD
Figg
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.
Cody J
CJ
Peer
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.
Michael C
MC
Sneller
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.
H Clifford
HC
Lane
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.
Jason L
JL
Yovandich
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.
Stephen P
SP
Creekmore
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.
Mario
M
Roederer
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.
Thomas A
TA
Waldmann
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D019409:Interleukin-15 / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
C569274:IL15 protein, human; D019409:Interleukin-15; D011994:Recombinant Proteins