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J Clin Oncol ; 33(1): 74-82, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25403209

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Interleucina-15/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Linfócitos T CD4-Positivos/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Febre/induzido quimicamente , Humanos , Infusões Intravenosas , Interleucina-15/efeitos adversos , Interleucina-15/genética , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto Jovem
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