Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma
Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma
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DOI：
10.1200/jco.20.1.142
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发表时间：
2002-01-01
影响因子：
45.3
通讯作者：
Rosenberg, SA
中科院分区：
文献类型：
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作者：
Toso, JF;Gill, VJ;Rosenberg, SA
目的：发现一株鼠伤寒沙门氏菌 (VNP20009) 通过染色体删除 purl 和 msbB 基因而减毒，可靶向肿瘤并抑制小鼠肿瘤生长。这些发现促成了目前对转移性癌症患者静脉输注 VNP20009 的 1 期研究。 患者和方法：在由 3 至 6 名患者组成的队列中，24 名转移性黑色素瘤患者和 1 名转移性肾细胞癌患者接受了 30 分钟静脉推注，其中含有 10(6) 至 10(9) cfu/m(2) 的 VNP20009。对患者进行剂量相关毒性、肿瘤内选择性复制和抗肿瘤作用的评估。结果：最大耐受剂量为3 x 10(8) cfu/m(2)。在接受1 x 109 cfu/m(2)的患者中观察到剂量限制性毒性，包括血小板减少、贫血、持续性菌血症、高胆红素血症、腹泻、呕吐、恶心、碱性磷酸酶升高和低磷血症。 VNP20009 诱导促炎细胞因子循环的剂量相关增加，例如白细胞介素 (IL)-1β、肿瘤坏死因子 α、IL-6 和 IL-12。在两名接受 1 x 10(9) cfu/m(2) 的患者和一名接受 3 x 10(8) cfu/m(2) 的患者中观察到局灶性肿瘤定植。所有患者均未经历客观的肿瘤消退，包括那些肿瘤定植的患者。结论：鼠伤寒沙门氏菌VNP20009菌株可以安全地施用于患者，并且在最高耐受剂量下，观察到了一些肿瘤定植。没有发现抗肿瘤作用，需要进行额外的研究来减少剂量相关的毒性并改善肿瘤定位。 (C) 2001 年美国临床肿瘤学会。
Purpose: A strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purl and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase 1 study of the intravenous infusion of VNP20009 to patients with metastatic cancer.Patients and Methods: In cohorts consisting of three to six patients, 24 patients with metastatic melanoma and one patient with metastatic renal cell carcinoma received 30-minute intravenous bolus infusions containing 10(6) to 10(9) cfu/m(2) of VNP20009. Patients were evaluated for dose-related toxicities, selective replication within tumors, and antitumor effects.Results: The maximum-tolerated dose was 3 x 10(8) cfu/m(2). Dose-limiting toxicity was observed in patients receiving 1 x 109 cfu/m(2), which included thrombocytopenia, anemia, persistent bacteremia, hyperbilirubinemia, diarrhea, vomiting, nausea, elevated alkaline phosphatase, and hypophosphatemia. VNP20009 induced a dose-related increase in the circulation of proinflammatory cytokines, such as interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, and IL-12. Focal tumor colonization was observed in two patients receiving 1 x 10(9) cfu/m(2) and in one patient receiving 3 x 10(8) cfu/m(2). None of the patients experienced objective tumor regression, including those patients with colonized tumors.Conclusion: The VNP20009 strain of Salmonella typhimurium can be safely administered to patients, and at the highest tolerated dose, some tumor colonization was observed. No antitumor effects were seen, and additional studies are required to reduce dose-related toxicity and improve tumor localization. (C) 2001 by American Society of Clinical Oncology.