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1.
J Clin Oncol ; 33(1): 74-82, 2015 Jan 01.
Article in English | MEDLINE | ID: mdl-25403209

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.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Cell Proliferation/drug effects , Interleukin-15/therapeutic use , Killer Cells, Natural/drug effects , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Area Under Curve , CD4-Positive T-Lymphocytes/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fever/chemically induced , Humans , Infusions, Intravenous , Interleukin-15/adverse effects , Interleukin-15/genetics , Killer Cells, Natural/metabolism , Lymphocyte Activation/drug effects , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Neoplasm Metastasis , Neoplasms/immunology , Neoplasms/metabolism , Neutropenia/chemically induced , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/therapeutic use , Treatment Outcome , Young Adult
2.
Blood ; 117(18): 4787-95, 2011 May 05.
Article in English | MEDLINE | ID: mdl-21385847

ABSTRACT

IL-15 uses the heterotrimeric receptor IL-2/IL-15Rß and the γ chain shared with IL-2 and the cytokine-specific IL-15Rα. Although IL-15 shares actions with IL-2 that include activation of natural killer (NK) and CD8 T cells, IL-15 is not associated with capillary leak syndrome, activation-induced cell death, or with a major effect on the number of functional regulatory T cells. To prepare for human trials to determine whether IL-15 is superior to IL-2 in cancer therapy, recombinant human IL-15 (rhIL-15) was produced under current good manufacturing practices. A safety study in rhesus macaques was performed in 4 groups of 6 animals each that received vehicle diluent control or rhIL-15 at 10, 20, or 50 µg/kg/d IV for 12 days. The major toxicity was grade 3/4 transient neutropenia. Bone marrow examinations demonstrated increased marrow cellularity, including cells of the neutrophil series. Furthermore, neutrophils were observed in sinusoids of enlarged livers and spleens, suggesting that IL-15 mediated neutrophil redistribution from the circulation to tissues. The observation that IL-15 administration was associated with increased numbers of circulating NK and CD8 central and effector-memory T cells, in conjunction with efficacy studies in murine tumor models, supports the use of multiple daily infusions of rhIL-15 in patients with metastatic malignancies.


Subject(s)
Interleukin-15/toxicity , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Blood Coagulation/drug effects , Bone Marrow/drug effects , Bone Marrow/pathology , Humans , Immunotherapy , Infusions, Intravenous , Interleukin-15/administration & dosage , Interleukin-15/immunology , Interleukin-15/pharmacokinetics , Liver/drug effects , Liver/pathology , Macaca mulatta , Neoplasms/immunology , Neoplasms/therapy , Neutropenia/blood , Neutropenia/chemically induced , Recombinant Proteins/administration & dosage , Recombinant Proteins/immunology , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/toxicity
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