title: Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 2B42, Bethesda, MD 20892, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Toso
authors.forename: Vee J
authors.initials: VJ
authors.lastname: Gill
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Schwartzentruber
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Frida
authors.initials: F
authors.lastname: Stock
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Freezer
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Morton
authors.forename: Claudia
authors.initials: C
authors.lastname: Seipp
authors.forename: Leah
authors.initials: L
authors.lastname: Haworth
authors.forename: Sharon
authors.initials: S
authors.lastname: Mavroukakis
authors.forename: Donald
authors.initials: D
authors.lastname: White
authors.forename: Susan
authors.initials: S
authors.lastname: MacDonald
authors.forename: John
authors.initials: J
authors.lastname: Mao
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D000907:Antibodies, Bacterial / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018988:Bacterial Translocation; D002292:Carcinoma, Renal Cell / Q000382:microbiology / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D015169:Colony Count, Microbial; D016207:Cytokines / Q000097:blood; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000382:microbiology / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D008875:Middle Aged; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000970:Antineoplastic Agents; D016207:Cytokines