AAV2-mediated in vivo immune gene therapy of solid tumours
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GENETIC VACCINES AND THERAPY
RESEARCH
Open Access
AAV2-mediated in vivo immune gene therapy of solid tumours Sara A Collins1,2, Alexandra Buhles1, Martina F Scallan2, Patrick T Harrison3, Deirdre M O’Hanlon4, Gerald C O’Sullivan1, Mark Tangney1*
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.
Introduction Cancer cells are capable of evading regular immune responses for a number of reasons: they can secrete immunosuppressive factors [1], there can be downregulation of antigen expression [2,3] or of major histocompatability complex (MHC) molecules [4,5] and also a lack of co-stimulation [6,7]. With the advent of gene therapy as a tool for cancer treatment, immunotherapyrelated approaches to stimulate immune responses against cancer cells include the transfer of immune stimulatory genes such as cytokines or costimulatory genes * Correspondence: [email protected] 1 Cork Cancer Research Centre, Mercy University Hospital and Leslie C. Quick Jnr. Laboratory, University College Cork, Cork, Ireland Full list of author information is available at the end of the article
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