Development of Anti-tumor Immunity against a Non-immunogenic Mammary Carcinoma through in Vivo Somatic GM-CSF, IL-2, and HSVtk Combination Gene Therapy

Brockstedt, Dirk G.; Diagana, Melissa; Zhang, Ying; Tran, Kimvan; Belmar, Nicole A.; Meier, Melinda; Yang, Adrienne; Boissière, Florence; Lin, Andy; Chiang, Yawen

doi:10.1006/mthe.2002.0722

Cited by 14 publications

(14 citation statements)

References 35 publications

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“…Our results confirm several literature reports which describe the higher efficacy of combined HSV-TK and cytokine (e.g. IL-2, GM-CSF or IL-12) gene therapy followed by GCV treatment in different types of cancer [20][21][22][23][24][25][26].…”

Section: Discussionsupporting

confidence: 94%

Systemic efficacy of combined suicide/cytokine gene therapy in a murine model of hepatocellular carcinoma

Stefani

Barzon

Castagliuolo

et al. 2005

Journal of Hepatology

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Section: Discussionsupporting

confidence: 94%

Systemic efficacy of combined suicide/cytokine gene therapy in a murine model of hepatocellular carcinoma

Stefani

Barzon

Castagliuolo

et al. 2005

Journal of Hepatology

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“…FasL is reported as an effector molecule that enhances the IL-12-mediated tumor regression (16,54). Expression of FasL requires Stat1 activation and is enhanced by IL-12 (26).…”

Section: Discussionmentioning

confidence: 99%

Stat1 Deficiency in the Host Enhances Interleukin-12–Mediated Tumor Regression

et al. 2006

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Signal transducer and activator of transcription 1 (Stat1) is considered a key transcription factor that inhibits tumorigenesis, and Stat1 activation in the host is required for interleukin-12 (IL-12)-mediated generation of CTL activity. Using syngeneic Stat1À/À C3H mice bearing SCCVII tumors in this study, we discovered opposite results. Stat1 deficiency in the host significantly enhances IL-12-mediated tumor regression, resulting in tumor eradication from 60% of SCCVII tumor-bearing mice and significant inhibition of tumor growth when compared with control treatment (P < 0.01). This effect is independent of both Stat1-activating cytokine IFN-; and Stat1-downstream effector molecule FasL because neither neutralization of IFN-; nor knocking out of FasL enhances or inhibits IL-12-mediated tumor regression. IL-12 induces a high intensity of tumor-specific CTL activity in Stat1-deficient mice (P < 0.01), increases the CD8 T-cell density in tumor bearing Stat1À/À mice, and induces a T-celldependent tumor regression. The increased CTL activity and the high-intensity infiltration of T cells into the tumors in IL-12-treated Stat1À/À mice are likely due to the longer survival than the same cells from wild-type mice. Together, the data show that inhibition of Stat1 expression in the host enhances tumor-local IL-12 gene therapy for regressing tumors. This conclusion provides a new concept for designing an effective treatment strategy. (Cancer Res 2006; 66(8): 4461-7)

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“…47 In vivo HSVtk/GCV electrogene therapy has previously been shown to suppress metastasis of mouse mammary carcinoma. 13,48 In addition, electrogene transfer of endostatin was recently reported to inhibit B16 melanoma lung metastasis. 49 In the present study, we found a significant decrease in microvessel density in the pEndo, pHSVtk/GCV and pEndo þ pHSVtk/GCV groups.…”

Section: Discussionmentioning

confidence: 99%

Electrogene therapy using endostatin, with or without suicide gene therapy, suppresses murine mammary tumor growth and metastasis

Morimoto

Doi

et al. 2006

Cancer Gene Ther

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Syngeneic inoculated metastatic mammary cancers received direct intratumoral injection of a plasmid vector containing either endostatin (pEndo) with or without a suicide gene (pHSVtk), pHSVtk alone or control vector once a week for 8 weeks. We applied electrogene transfer to the tumors after each injection and administered ganciclovir (GCV) to pHSVtk-transfected mice using an osmotic minipump. Anticancer efficacy was monitored using a variety of parameters, namely tumor volume, intratumoral microvessel density and DNA synthesis, number of mice with metastasis, and number of sites of metastasis per mouse. Tumor volume was significantly lower in all therapeutic groups, with the most effective growth suppression in the pEndo þ pHSVtk/GCV group. Lymph node metastasis was significantly less frequent in all therapeutic groups, whereas the multiplicity of lung metastases was significantly lower only in the pEndo and pEndo þ pHSVtk/GCV groups. All therapeutic groups showed significantly lower intratumor microvessel density and DNA synthesis. The pEndo and pEndo þ pHSVtk/GCV groups also showed a significant reduction in the numbers of dilated lymphatic vessels containing intralumenal tumor cells. Our data suggest that endostatin electrogene therapy alone or in combination with pHSVtk/GCV suicide gene therapy is more beneficial than suicide gene therapy alone. The observed antimetastatic activity of endostatin may be of high clinical significance in the treatment of metastatic breast cancer.

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Development of Anti-tumor Immunity against a Non-immunogenic Mammary Carcinoma through in Vivo Somatic GM-CSF, IL-2, and HSVtk Combination Gene Therapy

Cited by 14 publications

References 35 publications

Systemic efficacy of combined suicide/cytokine gene therapy in a murine model of hepatocellular carcinoma

Systemic efficacy of combined suicide/cytokine gene therapy in a murine model of hepatocellular carcinoma

Stat1 Deficiency in the Host Enhances Interleukin-12–Mediated Tumor Regression

Electrogene therapy using endostatin, with or without suicide gene therapy, suppresses murine mammary tumor growth and metastasis

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