Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma:: Biological and clinical results
Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma:: Biological and clinical results
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DOI：
10.1200/jco.2003.21.13.2508
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发表时间：
2003-07-01
影响因子：
45.3
通讯作者：
Yung, WKA
中科院分区：
文献类型：
--
作者：
Lang, FF;Bruner, JM;Yung, WKA
目的：脑肿瘤生物学研究进展表明，P53转移治疗人脑胶质瘤是一种新的治疗方法。因此，我们进行了用腺病毒载体(Ad-P53，INGN 201)进行P53基因治疗的I期临床试验。材料和方法：为了获得外源性P53在肿瘤内注射后在胶质瘤中转移和分布的分子信息，并确定脑内注射Ad-P53的毒性，我们采用了两步法。在第一阶段，通过植入的导管立体定向注射Ad-P53。第2期：肿瘤导管整块切除，术后空洞用Ad-P53处理。该方案提供了完整的经Ad-P53处理的生物标本，可以分析分子终点，并且由于切除腔本身注射了Ad-P53，因此可以观察患者的临床毒性。结果：在入选的15例患者中，12例同时接受了两种治疗阶段。所有患者的星形细胞瘤细胞核内均检测到外源性P53蛋白。外源性P53反式激活p21(CIP/WAF)并诱导细胞凋亡。然而，转基因细胞平均停留在注射部位5 mm以内。临床毒性最小，未达到最大耐受量。虽然大多数患者的抗腺病毒5型(Ad5)滴度增加，但没有证据表明全身性病毒传播。结论：瘤内注射Ad-P53允许外源性转移P53基因和表达功能性P53蛋白。然而，在评估的剂量和计划下，只有在注射部位很短的距离内才能发现转导细胞。尽管毒性很小，但这种药物的广泛分布仍然是一个重要的目标。(C)2003年，由美国临床肿瘤学会提供。
Purpose : Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201).Materials and Methods: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53-treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity.Results: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21(CIP/WAF) and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination.Conclusion: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal. (C) 2003 by American Society of Clinical Oncology.