Cytosine Deaminase/5-Fluorocytosine-Based Vaccination Against Liver Tumors: Evidence of Distant Bystander Effect

Pierrefite-Carle, Valérie; Baqué, Patrick; Gavelli, A; Mala, M.; Chazal, M; Gugenheim, Jean; Bourgeon, A; Milano, G.; Staccini, Pascal; Rossi, Bernard

doi:10.1093/jnci/91.23.2014

Cited by 37 publications

(40 citation statements)

References 10 publications

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“…33 In addition, the possibility of a CD/5-FC-induced immune mechanism mediating a systemic cytotoxic effect has been postulated but not fully delineated. 34,35 It is unknown to what degree each individual activity with respect to the peak concentration of intratumor 5-FU, the prolonged intratumor presence of 5-FU, or the oncolytic activity of the delivery vehicle will play in determining overall antitumor effect.…”

Section: Discussionmentioning

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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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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Section: Discussionmentioning

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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“…There is growing evidence that dendritic cells are important for induction of immunity (Todryk et al, 1999;Basu et al, 2000;Sauter et al, 2000). Other studies have suggested that CD4 cells (Caruso et al, 1993;Kuriyama et al, 1999a, b), natural killer cells (Pierrefite-Carle et al, 1999) and antibodies (Chen et al, 1999) also may play important roles. Futhermore, it appears that recognition of tumour antigens by T lymphocytes is not enough for efficient tumour cell killing and for elimination of the effect of tumour-induced immunosuppression (Horiguchi et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…A vaccination effect has been suggested to be important for the effect of the two chemotherapy models cytosine deaminase/5-fluorocytosine (Consalvo et al, 1995;Kuriyama et al, 1999b;Morris, 1999;Pierrefite-Carle et al, 1999) and herpes simplex virus thymidine kinase/ganciclovir (Barba et al, 1994;Yamamoto et al, 1997;Kuriyama et al, 1999a), and for the effect of photodynamic therapy (PDT) (Chen et al, 1997;Chen et al, 1999). These modalities induce tumour cell necrosis, and an inflammatory microenvironment, which is critical for eliciting an efficient immune response (Melcher et al, 1998;Todryk et al, 1999;Sauter et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

et al. 2005

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Previous studies in our laboratory have shown that interstitial laser thermotherapy (ILT) of an experimental liver tumour is superior to surgical excision, at least partly due to a laser-induced immunological effect. The aim of the present study was to investigate the time -response relationship of the ILT-induced immunisation and the cellular response of macrophages and lymphocytes. A dimethylhydrazine-induced adenocarcinoma was transplanted into the liver of syngeneic rats. Rats with tumour were treated 6 -8 days later (tumour size 0.25 -0.40 cm 3 ) with ILT of tumour or resection of the tumour-bearing lobe. Two groups of rats without tumour were treated with resection of a normal liver lobe or ILT of normal liver. A challenging tumour was implanted into the liver of each rat 2, 5 or 10 weeks after primary treatment. Rats were killed 6, 12 and 48 days (or earlier due to their condition) after challenge (n ¼ 8 in all groups). Immunohistochemical techniques were used to determine lymphocytes (CD8, CD4) and macrophages (ED1, ED2) in rats having had treatment of a primary tumour. Interstitial laser thermotherapy of the first tumour was followed by eradication of challenging tumour and absence of tumour spread. This contrasted with rapid growth and spread of challenging tumour in the other groups. In the challenging vital tumour tissue and in the interface between the tumour and surroundings, the number of ED1 macrophages and CD8 lymphocytes was higher in rats having been treated with the ILT of tumour than in those having undergone resection of the tumour-bearing lobe. The number of ED2 macrophages and CD4 lymphocytes was low and did not vary between these two groups. Interstitial laser thermotherapy elicited an immune response that eradicated a challenging tumour and was associated with increased numbers of tumour-infiltrating macrophages and CD8 lymphocytes.

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“…5,6 Finally, regression of distant non-transfected tumors can also be observed because of the triggering of a systemic antitumor immune response, which results in the destruction of the suicide geneexpressing tumor and tumor antigen release (distant bystander effect). [7][8][9][10][11][12] The induction of an antitumor immune response is essential for the treatment of a metastatic disease since introduction of the suicide gene in a single tumor can theoretically result in the regression of all the metastasis. According to the selected animal model and the applied suicide gene therapy system, T lymphocytes 9,10 and natural killer (NK) cells 8,11,12 have been reported to be involved in distant antitumor effect.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10][11][12] The induction of an antitumor immune response is essential for the treatment of a metastatic disease since introduction of the suicide gene in a single tumor can theoretically result in the regression of all the metastasis. According to the selected animal model and the applied suicide gene therapy system, T lymphocytes 9,10 and natural killer (NK) cells 8,11,12 have been reported to be involved in distant antitumor effect.…”

Section: Introductionmentioning

confidence: 99%

Cellular and molecular events associated with the antitumor response induced by the cytosine deaminase/5-fluorocytosine suicide gene therapy system in a rat liver metastasis model

et al. 2007

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The bacterial cytosine deaminase (CD) gene converts the non-toxic prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil. We have previously shown, in a rat liver metastasis model from colon carcinoma, that intratumoral injection of a CD-expressing plasmid into the animals followed by 5-FC treatment results in the regression of the treated tumor as well as distant uninjected tumors. The aim of this study was to further analyze the mechanisms associated with tumor regression induced upon application of suicide CD/5-FC strategy. Tumor regression was associated with an increased apoptosis, the recruitment of natural killer cells, CD4-and CD8 T lymphocytes within the tumors and an increased expression of several cytokines/chemokines mRNAs. These data indicate that the CD/5-FC suicide strategy is associated with the triggering of cellular and molecular events leading to an efficient antitumor immune response involving both innate and acquired immunity.

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Cytosine Deaminase/5-Fluorocytosine-Based Vaccination Against Liver Tumors: Evidence of Distant Bystander Effect

Abstract: Taken together, these results suggest the potential use of suicide gene-modified tumor cells as therapeutic vaccines against liver metastasis from colon carcinoma.

Cited by 37 publications

References 10 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

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

Cellular and molecular events associated with the antitumor response induced by the cytosine deaminase/5-fluorocytosine suicide gene therapy system in a rat liver metastasis model

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