Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer.
Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer.
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DOI：
10.1158/0008-5472.can-09-2762
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Russell SJ
中科院分区：
文献类型：
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作者：
Galanis E;Hartmann LC;Cliby WA;Long HJ;Peethambaram PP;Barrette BA;Kaur JS;Haluska PJ Jr;Aderca I;Zollman PJ;Sloan JA;Keeney G;Atherton PJ;Podratz KC;Dowdy SC;Stanhope CR;Wilson TO;Federspiel MJ;Peng KW;Russell SJ
麻疹病毒（MV）的Edmonston疫苗株在卵巢癌的临床前模型中显示出显着的抗肿瘤活性。我们设计MV表达标记肽癌胚抗原（MVCEA病毒），也允许在临床环境中实时监测肿瘤中的病毒基因表达。患有泰素和铂类难治性复发性卵巢癌且CEA水平正常的患者有资格参加这项I期试验。21例患者接受MV-CEA腹腔注射，每4周一次，最多6个周期，7个不同剂量水平（103-109 TCID 50）。我们没有观察到剂量限制性毒性、治疗诱导的免疫抑制、抗CEA抗体的产生、抗MV抗体滴度的增加或尿液或唾液中的病毒脱落。腹腔液和血清中CEA呈剂量依赖性升高。患者肿瘤标本的免疫组化分析显示，麻疹受体CD 46在15例患者中的13例过度表达。21例患者中有14例的最佳客观缓解为剂量依赖性疾病稳定，中位持续时间为92.5天（范围：54-277天）。5例患者CA-125水平显著降低。研究中患者的中位生存期为12.15个月（DELnth;范围，1.3-38.4个月），与该患者人群中预期的中位生存期6个月（DELnth）相比有利。我们的研究结果表明，腹腔注射MV-CEA耐受性良好，并在大量预治疗的复发性卵巢癌患者队列中产生剂量依赖性生物活性。
Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MVCEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (103–109 TCID50). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent stable disease in 14 of 21 patients with a median duration of 92.5 days (range, 54–277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (DELnths; range, 1.3–38.4 months), comparing favorably to an expected median survival of 6 months (DELnth) in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.