Improving cancer therapy by systemic administration of oncolytic viruses


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2011-2016

FUNDING AMOUNT

N/A

ABSTRACT

Background: We have shown that oncolytic viruses (OV) such as reovirus exert their anti-tumour effects by activating anti-tumour immunity, as well as by directly killing cancer cells. Reovirus is well advanced in the clinic, and our own laboratory and patient data has shown that cells in the blood can protect reovirus from neutralization following intravenous injection for delivery to tumours. Moreover, such carrier cells can be activated by reovirus to acquire immune-mediated anti-tumour effector function. Aims and Objectives: Within three specific aims, we will develop strategies to improve direct cytotoxic and immune-mediated therapy for melanoma and colorectal cancer by OV following systemic administration. The first two aims focus on tumour-targeted delivery of reovirus. Aim 1 seeks to enhance the protected delivery of reovirus to tumours by boosting the number of potential carrier cells (granulocytes, monocytes, lymphocytes, dendritic cells) in the blood, using ‘cell mobilizing drugs’ (granulocyte or granulocyte-macrophage colony stimulating factor, interleukin-2 and FMS-like tyrosine kinase 3 ligand). We will also test for activation of anti-tumour immune effector function in these cells by reovirus carriage, and for analogous activation by reovirus of normal resident liver immune cells which the virus accesses in vivo. Aim 2 further addresses improvement in immune- and vascular-mediated systemic reovirus therapy via combinations with immunomodulatory histone deacetylase inhibitors or chemotherapy, including in the context of vascular endothelial growth factor-secreting tumours. In Aim 3, we will test an alternative lymphoid-targeted systemic OV strategy, using ‘Viral Expressed Epitope Library’ (VEEL) vaccines. Vesicular stomatitis virus (replication competent or single cycle), will be used as a viral platform to express a full cDNA library derived from melanocyte/melanoma, autologous/allogeneic/xenogeneic tissue to treat melanoma. Here, the OV acts as an adjuvant to stimulate immune priming against multiple, undefined tumour-associated antigens expressed by the VEEL vaccine. Methods: Established murine in vivo and human in vitro preclinical models of therapy and anti-tumour immune priming will be used. These include readouts of purging of metastatic lymphoid metastases in mice, and experiments using tissue and blood from patients undergoing cancer surgery. This breadth of analysis is critical for testing whether common principles apply across different model systems, and underpins informed clinical translation. How the results will be used: The results of this work will be used to further optimize the use of systemic OV agents and inform the next generation of biological endpoint and therapeutic trials to build on our established clinical platform. More... »

Related SciGraph Publications

  • 2016-04. Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer in GENE THERAPY
  • 2015-09. Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia in LEUKEMIA
  • 2014-03. Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling in ONCOGENE
  • 2013-12. Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence in NATURE MEDICINE
  • 2013-05. Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin–paclitaxel doublet chemotherapy in GENE THERAPY
  • 2013-01. Measles virus causes immunogenic cell death in human melanoma in GENE THERAPY
  • 2012-12. Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway in BMC CANCER
  • 2012-10. Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples in MODERN PATHOLOGY
  • 2012-04. Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma in NATURE BIOTECHNOLOGY
  • 2012-01. Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer in BRITISH JOURNAL OF CANCER
  • 2012-01. Enhancing the immunogenicity of tumour lysate-loaded dendritic cell vaccines by conjugation to virus-like particles in BRITISH JOURNAL OF CANCER
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