Oncolytic viruses (OVs) are promising tumor-selective treatments, and the efficacy of OV therapies has been shown to depend heavily on the successful delivery and spread of these agents within the tumor mass to generate profound immunostimulatory effects. We have previously reported the potential of vanadium-based compounds such as vanadyl sulfate (VS) as immune-stimulatory enhancers of OV immunotherapy. These compounds, in conjunction with RNA-based OVs such as oncolytic VSVΔ51, improve viral spread and oncolysis, leading to long-term antitumor immunity and prolonged survival in resistant tumor models as previously reported. This effect is associated with a virus-induced antiviral type I IFN response shifting towards a type II IFN response. Here, the systemic impact and the relevant immunological changes following VS/VSVΔ51 combination therapy were investigated to understand the immunological mechanism of action leading to improved antitumor responses. We screened for the secretion of chemokines and cytokines in vivo to understand the mechanism of action regulating the recruitment of immune cells to the tumor in the CT26WT tumor model following treatment. Additionally, the antigen-specific immune response was investigated to further identify the relevant immunological changes following treatment with the VS+VSVΔ51 combination. Our data revealed that VS+VSVΔ51 combination therapy significantly increased the levels of IFN-γ and IL-6, and other key important pro-inflammatory cytokines and chemokines. Improved tumor antigen-specific T-cell responses were observed following the combined therapy. Supported by relevant immunological changes and as a proof of concept for the design of more effective therapeutic regimens, we found that local delivery of VSVΔ51 encoded with IL-12 or with other transgenes in combination with VS further improved therapeutic outcomes in a syngeneic CT26WT colon cancer model. We found that CD8+ T cells and Natural Killer (NK) cells play significant roles in establishing the therapeutic efficacy that we observed; Furthermore, engineering new and targeted therapeutic platforms to impact the antitumor immune response further improves the therapeutic benefits of the combined therapy.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/45697 |
| Date | 04 December 2023 |
| Creators | Alluqmani, Nouf |
| Contributors | Diallo, Jean-Simon |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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