First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agionist, to activate innate immune responses in patients with advanced cancer
First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agionist, to activate innate immune responses in patients with advanced cancer
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DOI：
10.1158/1078-0432.ccr-07-1443
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发表时间：
2007-12-01
影响因子：
11.5
通讯作者：
Miller, Jeffrey S.
中科院分区：
文献类型：
--
作者：
Dudek, Arkadiusz Z.;Yunis, Caria;Miller, Jeffrey S.
目的：对先天免疫理解的最新进展表明，需要一系列精心安排的事件来引发针对癌症的有效免疫应答。我们研究了Toll样受体7激动剂852 A（一种小分子咪唑喹啉）在晚期癌症患者中的全身给药。临床前研究表明，852 A刺激浆细胞样树突状细胞产生多种细胞因子，如IFN-α、白细胞介素-1受体拮抗剂和IFN-诱导蛋白-10。我们的目标是确定耐受剂量，药代动力学，药效学和免疫学的852 A在human.Experimental Design：符合条件的成年患者接受静脉注射852 A每周三次，2周。结果：25例患者（中位年龄55.0岁; 72%为男性）被纳入6个队列，接近水平为0.15至2.0 mg/m2。血清药物水平显示与剂量成比例，无药物蓄积证据。最大耐受剂量为1.2 mg/m2;较高剂量受疲劳和全身症状的限制。在所有接受剂量水平≥ 0.6 mg/m2的患者中观察到IFN-α、白细胞介素-1受体拮抗剂和IFN诱导蛋白-10、免疫活性和临床症状增加。发现药效学生物标志物与药代动力学变量之间存在显着相关性，并且观察到客观的临床反应。结论：852 A静脉注射剂量高达1.2 mg/m（2），每周三次，持续2周，安全，具有短暂或可逆的不良反应。这种新型Toll样受体7激动剂具有生物活性，有望刺激先天免疫反应。未来的试验有必要评估其在癌症患者中的治疗作用。
Purpose: Recent advances in the understanding of innate immunity suggest that an orchestrated sequence of events is required to elicit a productive immune response against cancer. We studied the systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimulates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-alpha, interleukin-1 receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose, pharmacokinetics, pharmacodynamics, and immunologic effects of 852A in humans.Experimental Design: Eligible adult patients with refractory solid organ tumors received i.v. 852A thrice weekly for 2 weeks. Patients who had responses or stable disease were eligible for additional cycles.Results: Twenty-five patients (median age, 55.0 years; 72% male) were enrolled in six cohorts at close levels of 0.15 to 2.0 mg/m(2). Serum drug levels showed dose proportionality and no evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m(2); higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-alpha, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were 2 observed in all patients receiving dose levels >= 0.6 mg/m(2). Significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables, and an objective clinical response was seen.Conclusions: 852A was safely administered i.v. at doses up to 1.2 mg/m(2) thrice weekly for 2 weeks with transient or reversible adverse effects. This novel Toll-like receptor 7 agonist is biologically active and holds promise for stimulating innate immune responses. Future trials are warranted to assess its therapeutic role in patients with cancer.