The effects of oncolytic Maraba virus (MG1) in malignant melanoma
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Embargo End Date
ICR Authors
Authors
Armstrong, E
Document Type
Thesis or Dissertation
Date
2022-07-31
Date Accepted
Abstract
Despite recent advances in the targeted and immunological treatment of melanoma, the incidence of this malignancy is increasing and is responsible for approximately 60,000 global deaths annually, highlighting the ongoing need for novel treatments. Oncolytic viruses (OV) have demonstrated the capacity for selective infection, replication and killing of tumour cells and the subsequent activation of anti-tumour immunity. Maraba virus (MG1) is a promising OV currently being investigated within phase I/II clinical trials.
This thesis investigates the anti-tumoural effects of MG1 using both in vitro melanoma cell line models and within an immunocompetent in vivo murine model. The ability of MG1 to reach the tumour, replicate within it and exert anti-tumour survival benefits using different routes of administration and in different in vivo models was explored. In addition, the ability of MG1 infection to induce immunogenic cell death in melanoma cell lines and the changes in the tumour immune mocroenvironment in vivo was examined. Finally, in an attempt to enhance OV therapeutic outcomes, rational combination treatments of MG1 with additional immunotherapeutic agents were investigated.
The results discussed here demonstrate that oncolytic MG1 was able to selectively infect, replicate inside and kill melanoma tumour cells, both in vitro and in vivo. Furthermore, in vivo, the tumour tropic properties of MG1 were illustrated, even despite the production of anti-viral neutralising antibodies. MG1 could generate hallmarks of immunogeneic cell death and alter the tumour immune microenvironment, at an immune cell, cytokine and RNA level. Intratumoural MG1 monotherapy was able to extend murine survival in a 4434, but not B16-F1, murine in vivo melanoma model. These survival gains could be enhanced through combining MG1 with an anti-PD-1 checkpoint inhibitor antibody.
Citation
2022
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Trans Immunotherapy