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Titolo:
EFFECTS OF SINGLE-DOSE INTERLEUKIN-12 EXPOSURE ON INTERLEUKIN-12-ASSOCIATED TOXICITY AND INTERFERON-GAMMA PRODUCTION
Autore:
LEONARD JP; SHERMAN ML; FISHER GL; BUCHANAN LJ; LARSEN G; ATKINS MB; SOSMAN JA; DUTCHER JP; VOGELZANG NJ; RYAN JL;
Indirizzi:
GENET INST INC,DEPT PRECLIN RES,87 CAMBRIDGE PK DR CAMBRIDGE MA 02140 GENET INST INC,DEPT PRECLIN RES CAMBRIDGE MA 02140 GENET INST INC,DEPT CLIN DEV CAMBRIDGE MA 02140 TUFTS UNIV,NEW ENGLAND MED CTR,DIV HEMATOL ONCOL BOSTON MA 02111 WYETH AYERST RES,DEPT DRUG SAFETY & METAB PRINCETON NJ 08543 UNIV ILLINOIS,COLL MED,HEMATOL ONCOL SECT CHICAGO IL 00000 UNIV CHICAGO,DEPT MED,HEMATOL ONCOL SECT CHICAGO IL 60637 MONTEFIORE MED CTR,ALBERT EINSTEIN CANC CTR,DEPT ONCOL BRONX NY 10467
Titolo Testata:
Blood
fascicolo: 7, volume: 90, anno: 1997,
pagine: 2541 - 2548
SICI:
0006-4971(1997)90:7<2541:EOSIEO>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
TUMOR-NECROSIS-FACTOR; RECOMBINANT HUMAN INTERLEUKIN-12; RENAL-CELL CARCINOMA; PHASE-I TRIAL; CANCER-PATIENTS; IFN-GAMMA; CYTOKINE; ANTITUMOR; MELANOMA; IL-12;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
J.P. Leonard et al., "EFFECTS OF SINGLE-DOSE INTERLEUKIN-12 EXPOSURE ON INTERLEUKIN-12-ASSOCIATED TOXICITY AND INTERFERON-GAMMA PRODUCTION", Blood, 90(7), 1997, pp. 2541-2548

Abstract

Interleukin-12 (IL-12) is a key regulator of cell-mediated immunity that has therapeutic potential in cancer and infectious disease. In a previous Phase 1 dose escalation study of a single test dose of recombinant human IL-12 (rhIL-12) followed 14 days later by cycles of five consecutive daily intravenous injections every 3 weeks, we showed that adose level up to 500 ng/kg could be administered with acceptable levels of safety. Based on these results, a Phase 2 study was conducted. In the Phase 2 study, however, administration of rhIL-12 at this same dose level resulted in severe toxicities with some patients unable to tolerate more than two successive doses. Of the 17 patients receiving rhIL-12 in the Phase 2 study, 12 patients were hospitalized and two patients died. A thorough scientific investigation to determine the causeof this unexpected toxicity failed to identify any difference in the drug products used or the patient populations enrolled in the Phase 1 and Phase 2 studies that could have accounted for the profound difference in toxicity. The focus of the investigation therefore shifted to the schedule of rhIL-12 administration. We determined that a single injection of rhIL-12 2 weeks before consecutive dosing included in the Phase 1 study, but not in the schedule of administration in the Phase 2 study, has a profound abrogating effect on IL-12-induced interferon-gamma (IFN-gamma) production and toxicity. This observation of schedule-dependent toxicity of IL-12 has been Verified in mice, as well as nonhuman primates. In this regard, a single injection of IL-12 before consecutive daily dosing protected mice and cynomolgus monkeys from acute toxicity including mortality and was associated with an attenuated IFN-gamma response. Because of this unique biologic response, careful attention to the schedule of administration is required to assure safe and effective clinical development of this highly promising cytokine. (C) 1997 by The American Society of Hematology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/11/20 alle ore 22:05:58