A phase I study of ultra low dose interleukin-2 and stem cell factor in patients with HIV infection or HIV and cancer
A phase I study of ultra low dose interleukin-2 and stem cell factor in patients with HIV infection or HIV and cancer
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DOI：
10.1158/1078-0432.ccr-06-0268
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发表时间：
2006-07-01
影响因子：
11.5
通讯作者：
Caligiuri, Michael A.
中科院分区：
文献类型：
--
作者：
Shah, Manisha H.;Freud, Aharon G.;Caligiuri, Michael A.
目的：超低剂量的白细胞介素-2（IL-2）可以激活体内组成型表达于CD 56（bright）自然杀伤（NK）细胞、CD 34（+）NK细胞前体和CD 4（+）CD 25（+）调节性T细胞（Tcells）上的高亲和力IL-2受体。我们先前已经在体外从CD 34（+）造血祖细胞产生CD 56（亮）NK细胞中显示了IL-2和干细胞因子（SCF）之间的协同作用，并且在体内临床前模型中显示了协同NK细胞扩增。为了确定这种细胞因子组合在体内的安全性、毒性和免疫调节，我们进行了首次人体I期研究。实验设计：使用900，000或650的IL-2进行I期剂量递增研究，结果：13例患者中有10例完成治疗; 4例出现3级疲劳或荨麻疹的剂量限制性毒性。IL-2和SCF联合使用的最大耐受剂量为IL-2 650，000 IU/m2/d和SCF 5 μ g/kg/d，每周3次。NK细胞扩增超过2倍的治疗; TCFs扩大近6倍，从baseline.Conclusions：IL-2与SCF的管理是安全的，耐受性良好，并导致艾滋病病毒或艾滋病病毒和癌症患者的淋巴细胞亚群的扩增;然而，NK细胞和Treg扩增的变化与这种细胞因子组合没有什么不同，比单独使用类似剂量的IL-2。
Purpose: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56(bright) natural killer (NK) cells, the CD34(+) NK cell precursor, and CD4(+)CD25(+) regulatory T cells (Tregs) in vivo. We have previously shown synergy between IL-2 and stem cell factor (SCF) in the generation of CD56(bright) NK cells from CD34(+) hemopoietic progenitor cells in vitro and showed synergistic NK cell expansion in an in vivo preclinical model. To determine the safety, toxicity, and immune modulation of this combination of cytokines in vivo, we conducted a first-in-man phase I study.Experimental Design: A phase I dose escalation study was conducted using IL-2 at 900,000 or 650,000 IU/m(2) /d for 8 weeks with 5 or 10 mu g/kg/d of SCF given thrice a week for 8 weeks in patients with HIV infection and/or cancer.Results: Ten of 13 patients completed therapy; four experienced the dose-limiting toxicities of grade 3 fatigue or urticaria. The maximum tolerated doses of IL-2 and SCF in combination is 650,000 IU/m(2) /d of IL-2 and 5 mu g/kg/d thrice a week of SCF. NK cells were expanded over 2-fold on therapy; Tregs were expanded nearly 6-fold from baseline.Conclusions: Administration of IL-2 with SCF is safe and well tolerated and leads to expansion of lymphocyte subsets in patients with HIV or HIV and cancer; however, the changes in NK cell and Treg expansion seen with this cytokine combination were no different than those seen with a similar dose of IL-2 alone.