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Effects of Single-Dose Interleukin-12 Exposure on Interleukin-12-Associated Toxicity and Interferon- Production
John P. Leonard,
Matthew L. Sherman,
Gerald L. Fisher,
Lynn J. Buchanan,
Glenn Larsen,
Michael B. Atkins,
Jeffrey A. Sosman,
Janice P. Dutcher,
Nicholas J. Vogelzang, and
John L. Ryan
From the Departments of Preclinical Research and Clinical Development, Genetics Institute, Cambridge; Division of Hematology/Oncology, Tufts-New England Medical Center, Boston, MA; the Department of Drug Safety and Metabolism, Wyeth-Ayerst Research, Princeton, NJ; Section of Hematology/Oncology, University of Illinois at Chicago, College of Medicine, Chicago; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL; and Albert Einstein Cancer Center/Montefiore Medical Center, Department of Oncology, Bronx, NY.
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 a dose 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 cause of 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- (IFN-) 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- 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.
Blood, Vol. 90 No. 7 (October 1), 1997:
pp. 2541-2548
© 1997 by The American Society of Hematology.
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