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Clinical Trial
. 2002 Jan 1;20(1):142-52.
doi: 10.1200/JCO.2002.20.1.142.

Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma

John F Toso  1 , Vee J Gill, Patrick Hwu, Francesco M Marincola, Nicholas P Restifo, Douglas J Schwartzentruber, Richard M Sherry, Suzanne L Topalian, James C Yang, Frida Stock, Linda J Freezer, Kathleen E Morton, Claudia Seipp, Leah Haworth, Sharon Mavroukakis, Donald White, Susan MacDonald, John Mao, Mario Sznol, Steven A Rosenberg
Affiliations
Clinical Trial

Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma

John F Toso et al. J Clin Oncol. .

Abstract

Purpose: A strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purI and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase I 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 10(9) 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.

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Figures

Fig 1.
Fig 1.
Serum cytokine concentrations were measured after the IV injection of VNP20009 at the doses specified. Serum was isolated from peripheral blood at the times indicated and analyzed for the presence of IL-6, IL-12, IL-1β, and TNF-α.
See this image and copyright information in PMC

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