Phase I Study of the Intravenous Administration of Attenuated Salmonella typhimurium to Patients With Metastatic Melanoma

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

doi:10.1200/jco.20.1.142

Cited by 428 publications

(353 citation statements)

References 20 publications

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“…14,15,[19][20][21] Recently, a phase I clinical trial involving 25 patients, who received intravenous infusion of VNP20009, defined a maximum tolerated dose of 3 Â 10 8 CFU/m 2 . 22 Colonization of tumor was detected in three patients however, objective tumor regression was not observed. Doserelated increases in circulation of interleukin 1 beta, tumor necrosis factor alpha, and interleukin 6 appeared to be associated with clinical toxicity, that is, hypotension, fever, thrombocytopenia, anemia, diarrhea, nausea, and vomiting.…”

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confidence: 87%

“…Doserelated increases in circulation of interleukin 1 beta, tumor necrosis factor alpha, and interleukin 6 appeared to be associated with clinical toxicity, that is, hypotension, fever, thrombocytopenia, anemia, diarrhea, nausea, and vomiting. 22,23 A second study involved direct intratumoral administration of VNP20009. Approximately 2 weeks following the administration of VNP20009, VNP20009 could be detected in biopsies of most injected lesions, and in some necrosis, inflammation, and/or regression was observed.…”

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confidence: 99%

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Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

et al. 2003

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We performed a pilot trial in refractory cancer patients to investigate the feasibility of intratumoral injection of TAPET-CD, an attenuated Salmonella bacterium expressing the E. coli cytosine deaminase gene. A total of three patients received three dose levels of TAPET-CD (3 Â 10 6 -3 Â 10 7 CFU/m 2 ) via intratumoral injection once every 28 days as long as progression of disease or intolerable toxicity was not observed. From days 4 to 14 of each 28 day cycle, patients also received 5-fluorocytosine (5-FC) at a dose of 100 mg/kg/day p.o. divided three times daily. Six cycles of treatment were administered. No significant adverse events clearly attributable to TAPET-CD were demonstrated. Two patients had intratumor evidence of bacterial colonization with TAPET-CD, which persisted for at least 15 days after initial injection. Conversion of 5-FC to 5-fluorouracil (5-FU) as a result of cytosine deaminase expression was demonstrated in these two patients. The tumor to plasma ratio of 5-FU for these two colonized patients was 3.0, demonstrating significantly increased levels of 5-FU at the site of TAPET-CD colonization and insignificant systemic spread of the bacteria. In contrast, the tumor to plasma ratio of 5-FU of the patient who did not show colonization of TAPET-CD was less than 1.0. These results support the principle that a Salmonella bacterium can be utilized as a delivery vehicle of the cytosine deaminase gene to malignant tissue and that the delivered gene is functional (i.e. able to convert 5-FC to 5-FU) at doses at or below 3 Â 10 7 CFU/m 2 .

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confidence: 87%

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confidence: 99%

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

et al. 2003

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“…6,7 Attenuated forms of Salmonella typhimurium have been tested in clinical trials. 11 For most of the bacteria used, the precise mechanism of action remains unclear. However, the anticancer properties of Salmonella are not mediated by invasion of the tumour cells since Salmonella mutants with impaired ability to invade in vitro melanoma cells had no reduction in their antitumour activity in vivo.…”

Section: Invasive E Coli As a Therapeutic Delivery Vector Rj Critchlmentioning

confidence: 99%

“…11 VNP20009 demonstrated marked toxicity when injected above 3 Â 10 8 CFU/m 2 . At this dose, some tumour colonization was observed but objective tumour regression was not observed in any of the patients, 11 suggesting that the safety features of the formulation need to be improved to be able to reach a therapeutically relevant dose.…”

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confidence: 99%

Potential therapeutic applications of recombinant, invasive E. coli

et al. 2004

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“…and i.v. administration) is being tested in clinical phase I studies (Cunningham and Nemunaitis, 2001;Toso et al, 2002). From the perspective of the broader application of the novel anticancer treatment (eg, optimisation of protocol, combining with radiotherapy or chemotherapy), the non-invasive MR methodology thus offers a significant advance for individual guidance and longitudinal monitoring of treatment.…”

Section: Resultsmentioning

confidence: 99%

Non-invasive 19F MR spectroscopy of 5-fluorocytosine to 5-fluorouracil conversion by recombinant Salmonella in tumours

et al. 2003

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The aim of this study was to evaluate the applicability of fluorine-19 magnetic resonance spectroscopy ( 19 F MRS) for monitoring in vivo the conversion of 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) after using an attenuated Salmonella Typhimurium strain recombinant to provide cytosine deaminase (TAPET-CD). The 19 F MRS measurements were done on mice bearing the human colon tumour xenograft (HCT116). The intratumoural conversion is greater when TAPET-CD/5-FC is delivered intratumourally (i.tu.) than when TAPET-CD is delivered intravenously (i.v.) and 5-FC intraperitoneally (i.p.). Repeat measurements of the same tumour also yielded important information on the tumour colonization by TAPET-CD through the correlated 5-FC to 5-FU conversion efficacy. The in vivo MRS spectra were confirmed by in vitro 19 F MRS of perchloric acid extracts of the tumour tissue. No 5-FU metabolites were detectable in vivo in the tumours. However, the in vitro measurements revealed, besides 5-FC and 5-FU, the presence of small amounts of catabolites. Finally, spectra obtained in vitro from liver extracts of tumour-bearing mice treated i.tu. with TAPET-CD/5-FC showed no 5-FU and only little amounts of catabolites. Our data illustrate most importantly the potential of 19 F MRS to monitor biologically-based treatments involving cytosine deaminase.

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Phase I Study of the Intravenous Administration of Attenuated Salmonella typhimurium to Patients With Metastatic Melanoma

Abstract: 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.

Cited by 428 publications

References 20 publications

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

Potential therapeutic applications of recombinant, invasive E. coli

Non-invasive 19F MR spectroscopy of 5-fluorocytosine to 5-fluorouracil conversion by recombinant Salmonella in tumours

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