AAV2-mediated in vivo immune gene therapy of solid tumours

Hdl Handle:
http://hdl.handle.net/10147/120426
Title:
AAV2-mediated in vivo immune gene therapy of solid tumours
Authors:
Collins, Sara A; Buhles, Alexandra; Scallan, Martina F; Harrison, Patrick T; O'Hanlon, Deirdre M; O'Sullivan, Gerald C; Tangney, Mark
Issue Date:
20-Dec-2010
URI:
http://hdl.handle.net/10147/120426
Abstract:
Abstract Background Many strategies have been adopted to unleash the potential of gene therapy for cancer, involving a wide range of therapeutic genes delivered by various methods. Immune therapy has become one of the major strategies adopted for cancer gene therapy and seeks to stimulate the immune system to target tumour antigens. In this study, the feasibility of AAV2 mediated immunotherapy of growing tumours was examined, in isolation and combined with anti-angiogenic therapy. Methods Immune-competent Balb/C or C57 mice bearing subcutaneous JBS fibrosarcoma or Lewis Lung Carcinoma (LLC) tumour xenografts respectively were treated by intra-tumoural administration of AAV2 vector encoding the immune up-regulating cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and the co-stimulatory molecule B7-1 to subcutaneous tumours, either alone or in combination with intra-muscular (IM) delivery of AAV2 vector encoding Nk4 14 days prior to tumour induction. Tumour growth and survival was monitored for all animals. Cured animals were re-challenged with tumourigenic doses of the original tumour type. In vivo cytotoxicity assays were used to investigate establishment of cell-mediated responses in treated animals. Results AAV2-mediated GM-CSF, B7-1 treatment resulted in a significant reduction in tumour growth and an increase in survival in both tumour models. Cured animals were resistant to re-challenge, and induction of T cell mediated anti-tumour responses were demonstrated. Adoptive transfer of splenocytes to naïve animals prevented tumour establishment. Systemic production of Nk4 induced by intra-muscular (IM) delivery of Nk4 significantly reduced subcutaneous tumour growth. However, combination of Nk4 treatment with GM-CSF, B7-1 therapy reduced the efficacy of the immune therapy. Conclusions Overall, this study demonstrates the potential for in vivo AAV2 mediated immune gene therapy, and provides data on the inter-relationship between tumour vasculature and immune cell recruitment.
Item Type:
Article
Language:
en
Keywords:
GENETICS; CANCER
ISSN:
http://dx.doi.org/10.1186/1479-0556-8-8

Full metadata record

DC FieldValue Language
dc.contributor.authorCollins, Sara Aen
dc.contributor.authorBuhles, Alexandraen
dc.contributor.authorScallan, Martina Fen
dc.contributor.authorHarrison, Patrick Ten
dc.contributor.authorO'Hanlon, Deirdre Men
dc.contributor.authorO'Sullivan, Gerald Cen
dc.contributor.authorTangney, Marken
dc.date.accessioned2011-01-26T16:36:22Z-
dc.date.available2011-01-26T16:36:22Z-
dc.date.issued2010-12-20-
dc.identifier.issnhttp://dx.doi.org/10.1186/1479-0556-8-8-
dc.identifier.urihttp://hdl.handle.net/10147/120426-
dc.description.abstractAbstract Background Many strategies have been adopted to unleash the potential of gene therapy for cancer, involving a wide range of therapeutic genes delivered by various methods. Immune therapy has become one of the major strategies adopted for cancer gene therapy and seeks to stimulate the immune system to target tumour antigens. In this study, the feasibility of AAV2 mediated immunotherapy of growing tumours was examined, in isolation and combined with anti-angiogenic therapy. Methods Immune-competent Balb/C or C57 mice bearing subcutaneous JBS fibrosarcoma or Lewis Lung Carcinoma (LLC) tumour xenografts respectively were treated by intra-tumoural administration of AAV2 vector encoding the immune up-regulating cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and the co-stimulatory molecule B7-1 to subcutaneous tumours, either alone or in combination with intra-muscular (IM) delivery of AAV2 vector encoding Nk4 14 days prior to tumour induction. Tumour growth and survival was monitored for all animals. Cured animals were re-challenged with tumourigenic doses of the original tumour type. In vivo cytotoxicity assays were used to investigate establishment of cell-mediated responses in treated animals. Results AAV2-mediated GM-CSF, B7-1 treatment resulted in a significant reduction in tumour growth and an increase in survival in both tumour models. Cured animals were resistant to re-challenge, and induction of T cell mediated anti-tumour responses were demonstrated. Adoptive transfer of splenocytes to naïve animals prevented tumour establishment. Systemic production of Nk4 induced by intra-muscular (IM) delivery of Nk4 significantly reduced subcutaneous tumour growth. However, combination of Nk4 treatment with GM-CSF, B7-1 therapy reduced the efficacy of the immune therapy. Conclusions Overall, this study demonstrates the potential for in vivo AAV2 mediated immune gene therapy, and provides data on the inter-relationship between tumour vasculature and immune cell recruitment.-
dc.language.isoenen
dc.subjectGENETICSen
dc.subjectCANCERen
dc.titleAAV2-mediated in vivo immune gene therapy of solid tumoursen
dc.typeArticleen
dc.language.rfc3066en-
dc.rights.holderCollins et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2011-01-05T08:01:23Z-
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