Replicating viruses for the treatment of cancer have a number of advantages over
traditional therapeutic modalities. They are highly targeted, self-amplifying, and have the
added potential to act as both gene-therapy delivery vehicles and oncolytic agents. ORFV,
(Parapoxvirus ovis, or Orf virus) is the prototypic species of the Parapoxvirus genus,
causing a benign disease in its natural ungulate host. ORFV possesses a number of unique
properties that make it an ideal viral backbone for the development of a cancer therapeutic: it
is safe in humans, has the ability to cause repeat infections even in the presence of antibody,
and it induces a potent Th-1 dominated immune response. Here I show for the first time that
live replicating ORFV induces an anti-tumour immune response in multiple syngeneic mouse
models of cancer that is mediated largely by the potent activation of both cytokine-secreting,
and tumouricidal natural killer (NK) cells. I have also highlighted the clinical potential of the
virus by demonstration of human cancer cell oncolysis including efficacy in an A549
xenograft model of cancer. The mechanism of ORFV-mediated activation of NK cells has
been explored, where I have demonstrated activation via direct ex vivo infection of NK cells.
I have also highlighted ORFV-mediated activation of dendritic cells (DCs), both in vivo and
by direct infection ex vivo. An in vivo DC depletion study demonstrated an indirect
mechanism for ORFV NK cell activation, where in the absence of DCs, NK cell activation
was diminished, as was the ability of ORFV to clear lung metastases. The ORFV innate
immune stimulatory profile has been harnessed for therapeutic application in an experimental
surgery model of cancer, where ORFV therapy at the time of surgery reduces the number of
cancer metastases. These data highlight the clinical potential of a live, immune stimulating
Parapoxvirus therapeutic.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU-OLD./22925 |
| Date | 27 June 2012 |
| Creators | Rintoul, Julia |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thèse / Thesis |
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