Investigating Radiation in Combination with Oncolytic Vaccinia Virus to Improve the Treatment of Glioblastoma

• Author / Creator

  Storozynsky, Quinn

• Glioblastoma (GBM) is a malignant and immune-suppressed brain cancer that remains incurable despite the current standard of care. Radiotherapy is a mainstay of GBM treatment, however invasive cancer cells outside the irradiated field and radioresistance preclude complete eradication of GBM cells. Further, radiation induces cellular senescence in GBM cells. Senescent cells cease proliferation but remain viable and are implicated in promoting tumor progression. Oncolytic virus (OV) therapy harnesses tumor-selective viruses to spread through and destroy tumors while stimulating antitumor immune responses, and thus has potential for use following radiotherapy. We demonstrate that oncolytic ΔF4LΔJ2R vaccinia virus (VACV) replicates in and induces cytotoxicity of irradiated brain tumor initiating cells in vitro. Importantly, a single 10 Gy dose of radiation combined with ΔF4LΔJ2R VACV produced considerably superior anticancer effects relative to either monotherapy when treating immune-competent orthotopic CT2A-luc mouse models–significantly extending survival and curing the majority of mice. Following intracranial tumor challenges, mice cured by the combination displayed significantly increased survival relative to naïve age-matched controls, with some complete rejections. Further, the combination therapy was associated with an increased ratio of CD8+ effector T cells to regulatory T cells compared to either monotherapy. Moreover, it is unknown how radiation-induced cellular senescence may impact the oncolytic properties of VACV-based OVs used in combination with radiotherapy. The interaction of viruses with senescent cells is nuanced; some viruses exploit the senescent state to their benefit, while others are hampered, indicating senescence-associated antiviral activity. To better understand this, we induced cellular senescence by treating GBM cells with radiation, and then evaluated the growth kinetics, infectivity, and cytotoxicity of oncolytic ∆F4L∆J2R VACV, as well as wild-type VACV for comparison, in irradiated senescence-enriched and non-irradiated human GBM cell lines. Our results show that both viruses display attenuated oncolytic activities in irradiated senescence-enriched GBM cell populations compared to non-irradiated controls. Taken together, these findings validate the use of radiation with an oncolytic ΔF4LΔJ2R VACV to improve treatment of this malignant brain cancer and indicate that radiation-induced cellular senescence is associated with antiviral activity–highlighting important considerations for the combination of VACV-based oncolytic therapies with senescence-inducing agents such as radiotherapy.

• Subjects / Keywords

  • Glioblastoma
  • Oncolytic virus
  • Radiotherapy
  • Vaccinia virus
  • Immunotherapy

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-wxbd-7j28

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.