Suppression of the immune response to an adenovirus vector and enhancement of intratumoral transgene expression by low-dose etoposide
Suppression of the immune response to an adenovirus vector and enhancement of intratumoral transgene expression by low-dose etoposide
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DOI：
10.1038/sj.gt.3300564
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发表时间：
1998-02-01
期刊：
影响因子：
5.1
通讯作者：
Roth, JA
中科院分区：
文献类型：
--
作者：
Bouvet, M;Fang, B;Roth, JA
腺病毒载体因其在基因转移中的效率而被广泛应用于基因治疗试验。然而，它们的使用受到细胞和体液免疫反应的限制，这些反应导致暂时的转基因表达，并降低了重复给药的效果。我们假设，某些常用于治疗癌症患者的溶瘤药物可以抑制对腺病毒载体的免疫反应，并使重复腺病毒介导的癌症基因治疗成为可能。用C3H小鼠检测了依托泊苷和环磷酰胺对腺病毒载体的体液和细胞免疫应答的抑制作用。在用依托泊苷或环磷酰胺治疗的腺病毒免疫的动物中，监测了瘤内转基因的表达。与未治疗组相比，依托泊苷2 mg/kg/d、10 mg/kg/d或环磷酰胺10 mg/kg/d处理组小鼠的抗腺病毒中和抗体和病毒转导细胞的细胞毒性T淋巴细胞(CTL)活性均受到显著抑制(P<；0.05)。与未处理的小鼠或环磷酰胺2 mg/kg/d处理的小鼠相比，处理组小鼠的基因转导面积显著增加(P<；0.05)。我们的结果表明，在同时接受化疗的癌症患者中，重复腺病毒介导的基因治疗是可以实现的。
Adenoviral vectors are commonly used in gene therapy trials because of their efficiency in gene transfer. However, their use is limited by cellular and humoral immune responses that result in temporary transgene expression and reduced efficacy of repeated vector administration. We hypothesized that certain oncolytic agents commonly used to treat cancer patients could suppress the immune response to adenoviral vectors, and enable repeated adenovirus-mediated cancer gene therapy. Etoposide and cyclophosphamide were tested for their ability to suppress the humoral and cellular immune responses to an adenoviral vector in immunocompetetn C3H mice. Intratumoral transgene expression was monitored in adenovirus-immunized animals treated with etoposide or cyclophosphamide. Neutralizing antibodies to adenovirus and cytotoxic T lymphocyte (CTL) lysis of virally transduced cells were significantly suppressed in mice treated with etoposide at 2 or 10 mg/kg/day or cyclophosphamide at 10 mg/kg/day compared with untreated mice (P < 0.05). Significantly larger areas of gene transduction were observed in treated animals compared with untreated mice or the mice treated with cyclophosphamide at 2 mg/kg/day (P < 0.05). Our results suggest that repeated adenovirally mediated gene therapy is achievable in cancer patients who are concurrently undergoing treatment with chemotherapy.