Phase I study of the sequential combination of interleukin-12 and interferon alfa-2b in advanced cancer: Evidence for modulation of interferon signaling pathways by interleukin-12

被引:20
作者
Eisenbeis, CF
Lesinski, GB
Anghelina, M
Parihar, R
Valentino, D
Liu, J
Nadella, P
Sundaram, P
Young, DC
Sznol, M
Walker, MJ
Carson, WE
机构
[1] Ohio State Univ, Dept Surg, Div Surg Oncol, Columbus, OH 43210 USA
[2] Ohio State Univ, Div Hematol & Oncol, Columbus, OH 43210 USA
[3] Ohio State Univ, Div Human Canc Genet, Columbus, OH 43210 USA
[4] Ohio State Univ, Arthur G James Canc Hosp, Ctr Biostat, Columbus, OH 43210 USA
[5] Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43210 USA
[6] Yale Univ, New Haven, CT 06520 USA
关键词
D O I
10.1200/JCO.2005.02.1691
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-gamma on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs). Patients and Methods Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN-a-2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN-alpha-2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN-gamma production. Peripheral blood was drawn for measurement of plasma IFN-gamma and the induction of Jak-STAT signal transduction in PBMCs. Results No IL-12- or IFN-alpha-related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN-gamma by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN-gamma achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021). Conclusion The combination of rhIL-12 and IFN-a-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-alpha-induced Jak-STAT signal transduction in patient PBMCs.
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页码:8835 / 8844
页数:10
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