Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoural cytokine expression

Vile, Richard G.; Castleden, Simon; Marshall, John F.; Camplejohn, Richard S.; Upton, Carol; Chong, Heung

doi:10.1002/(sici)1097-0215(19970410)71:2<267::aid-ijc23>3.0.co;2-d

Cited by 175 publications

(56 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The presence of an intense in¯ammatory in®ltrate has been described in the regressing tumours of immunocompetent animals treated with GDEPT systems (HSV TK/GCV, Caruso et al, 1993;Vile et al, 1997;Yamamoto et al, 1997;CD/5-FC, Consalvo et al, 1995;Kuriyama et al, 1999a). Moreover, it has been noticed that the bystander effect was signi®cantly reduced in immunode®cient athymic mice (Vile et al, 1994;Gagandeep et al, 1996;Pavlovic et al, 1996;Ramesh et al, 1996;Bi et al, 1997;Kuriyama et al, 1999a) and after sublethal irradiation (Ramesh et al, 1996).…”

Section: The Bystander Effectmentioning

confidence: 99%

“…Cotransfection of cytokine-and suicide genebased vectors followed by prodrug treatment has met with varying results (Chen et al, 1995;Castleden et al, 1997;Coll et al, 1997;Moriuchi et al, 1998;Nanni et al, 1998;Pizzato et al, 1998;Cao et al, 2000). Combined adenoviral delivery of CD/5-FC and murine interleukin-2 (IL-2) to mice inoculated with erythroleukemia cells induced more potent tumour growth inhibition and longer survival than the separate treatments (Ju et al, 1998).…”

Section: The Bystander Effectmentioning

confidence: 99%

“…Preclinical studies using adeno-and retroviral vectors were performed in many different animal models and successful results were reported for established rodent liver metastases (Caruso et al, 1993), murine hepatocellular carcinomas (Kuriyama et al, 1999 b), rodent glioblastomas (Short et al, 1990;Culver et al, 1992), human head and neck carcinomas (O'Malley, 1995), human mesotheliomas (Smythe et al, 1995) and several other tumour types. Nevertheless, the HSV TK/ GCV-induced mechanisms of cell killing have not been completely elucidated, and both apoptotic (Freeman et al, 1993;Wei et al, 1999;Beltinger et al, 2000;Thust et al, 2000) and non-apoptotic (Kaneko and Tsukamoto, 1995;Vile et al, 1997;Melcher et al, 1998) pathways have been reported.…”

Section: Herpes Simplex Virus Thymidine Kinase/ganciclovirmentioning

confidence: 99%

“…It is likely that a major part in the in vivo bystander killing is played by the host immune system. HSV TK/GCV treatment resulted in in®ltration of CD4 + and CD8 + T cells and macrophages, as well as increased expression of IL-2, IL-12, interferong, tumour necrosis factor-a and granulocyte/macrophage colony-stimuling factor, suggesting that the induced cell killing creates a cytokine-rich immunostimulatory environment (Gagandeep et al, 1996;Vile et al, 1997). The generation of immunostimulatory signals in vivo appeared to be predominant in nonapoptotic tumours, and associated with the induction of genes of the inducible heat shock protein family (Melcher et al, 1998).…”

Section: Herpes Simplex Virus Thymidine Kinase/ganciclovirmentioning

confidence: 99%

See 3 more Smart Citations

Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

2001

View full text Add to dashboard Cite

Gene therapy of cancer is a novel approach with the potential to selectively eradicate tumour cells, whilst sparing normal tissue from damage. In particular, gene-directed enzyme prodrug therapy (GDEPT) is based on the delivery of a gene that encodes an enzyme which is non-toxic per se, but is able to convert a prodrug into a potent cytotoxin. Several GDEPT systems have been investigated so far, demonstrating effectiveness in both tissue culture and animal models. Based on these encouraging results, phase I/II clinical trials have been performed and are still ongoing. The aim of this review is to summarise the progress made in the design and application of GDEPT strategies. The most widely used enzyme/prodrug combinations already in clinical trials (e.g., herpes simplex 1 virus thymidine kinase/ganciclovir and cytosine deaminase/5-¯uorocytosine), as well as novel approaches (carboxypeptidase G2/CMDA, horseradish peroxidase/indole-3-acetic acid) are described, with a particular attention to translational research and early clinical results.

show abstract

Section: The Bystander Effectmentioning

confidence: 99%

Section: The Bystander Effectmentioning

confidence: 99%

Section: Herpes Simplex Virus Thymidine Kinase/ganciclovirmentioning

confidence: 99%

Section: Herpes Simplex Virus Thymidine Kinase/ganciclovirmentioning

confidence: 99%

See 2 more Smart Citations

Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

2001

View full text Add to dashboard Cite

show abstract

“…T-cells, and CD8 ? T-cells, and elicits an anti-tumor inflammatory response [26]. However, the GCV clinical trial results revealed that delivery of HSV.tk alone by adenoviral vehicles into tumors did not achieve the required antitumor efficacy due to limited infection and lack of potency.…”

Section: Discussionmentioning

confidence: 99%

STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy

Ahn

Shin

et al. 2012

Clin Exp Metastasis

View full text Add to dashboard Cite

Aberrant activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling has been shown to be associated with uncontrolled cell proliferation and suppression of host-immune surveillance. Conversely, silencing STAT3 can have the dual effects of inhibiting cancer cell proliferation and inducing anti-tumor immune responses. Here, we report on the effects of STAT3 silencing on suicide gene therapy with thymidine kinase (tk). STAT3 silencing by siRNA inhibited the proliferation of AGS human gastric cancer cells through G1 cell cycle arrest, decreased levels of immune-suppressive cytokines, and increased levels of immune-activating cytokines. CT26 mouse colon adenocarcinoma cells, in which STAT3 expression was knocked-down by a STAT3 shRNA-containing lentivirus, grew more slowly in syngenic model Balb/c mice than control CT26 cells. Moreover, we found that STAT3 silencing augmented the efficacy of suicide gene therapy in CT26 cell xenografted mice. When we administrated adenoviruses harboring the herpes simplex virus thymidine kinase gene (Ad5.CMV.HSV.tk) into STAT3-silenced CT26 cell tumors, extensive apoptosis was observed and there was a significant reduction in the size of CT26 cell tumors. STAT3 silencing also enhanced the recruitment and cytotoxic activity of CD3(+)CD8(+) T-cells, and changed the cytokine expression pattern of CT26 cell tumors, reflecting augmentation of anti-cancer immune responses. We conclude that combining suicide gene therapy with STAT3 silencing can result in enhanced anti-cancer effects.

show abstract

Enhancement of tumor killing using a combination of tumor immunization andHSV-tk suicide gene therapy

et al. 1999

View full text Add to dashboard Cite

Tumor cells genetically modified with the herpes simplex virus thymidine kinase (HSV‐tk) gene in combination with ganciclovir (GCV) demonstrate a “bystander effect”. Previous attempts to enhance the bystander tumor killing by combining cytokine genes with HSV‐tk/GCV have met with varying results. The present study was designed to determine the effects of tumor immunization in combination with HSV‐tk gene‐modified tumor cells and GCV on tumor killing and to determine if the bystander tumor killing could be enhanced. Tumor‐bearing mice immunized with syngeneic tumor (KBALB) prior to treatment with an i.p. injection of xenogeneic HSV‐tk gene‐modified tumor cells (PA‐1STK) had prolonged animal survival (group 4, 56.4 days). In contrast, unimmunized tumor‐bearing mice (group 2) or tumor‐bearing mice immunized to the xenogeneic PA‐1STK tumor cells (group 5) showed a mean survival of about 27 days after receiving an i.p. injection of PA‐1STK cells and GCV. Control groups, which were either not immunized and did not receive HSV‐tk cells (group 1) or immunized but treated only with GCV (group 3) showed short survival (16–18 days). Analysis of tumors for cytokine mRNA expression revealed increased TNF‐α and IL‐1α mRNA expression in group 4 mice. Furthermore, IL‐2 mRNA expression was detectable on days 2 and 4 only in group 4 mice. Immunophenotypic analysis for tumor‐infiltrating lymphocytes demonstrated an increase in macrophage (4%, p = 0.0001) and T cells (1.8%, p < 0.001) in group 4 mice with an enhanced T‐cell response as compared with mice from groups 1, 2 and 3. Our results demonstrate that tumor immunization combined with HSV‐tk/GCV treatment results in increased animal survival with enhanced immune response. Furthermore, the cytokine milieu observed in the present study can modulate the tumor micro‐environment in vivo from one that is immunosuppressive to one that is immune‐stimulatory. Int. J. Cancer 80:380–386, 1999. © 1999 Wiley‐Liss, Inc.

show abstract

Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoural cytokine expression

Cited by 175 publications

References 14 publications

Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy

Enhancement of tumor killing using a combination of tumor immunization andHSV-tk suicide gene therapy

Contact Info

Product

Resources

About