Combination Radiation Therapy and Oncolytic Vaccinia Virus Therapy in Preclinical Models of Glioma

• Author / Creator

  Fung, Rachel D

• Gliomas are the most common primary malignant brain tumour in adults, with glioblastoma multiforme (GBM), the most common and most deadly form of glioma, making up over half of all diagnosed cancers in the brain/central nervous system. The standard of care for gliomas has remained unchanged for the past decade: maximal surgical excision is the primary means of therapy, followed by post-operative radiotherapy and concurrent chemotherapy with the alkylating agent temozolomide (TMZ). Despite this, however, the prognosis for malignant gliomas, and in particular GBMs, is incredibly poor. As such, improved therapeutic options are sorely needed, especially those with a high safety profile and an ability to target tumour microextensions missed by surgery and radiotherapy. Oncolytic virotherapy is an exciting new field in cancer therapeutics, with the first oncolytic virus approved by the Food and Drug Administration in 2015 and many more undergoing clinical trials currently. In our lab, a genetically engineered vaccinia virus (VACV) has been proposed as an addition to this expanding field of oncolytic virotherapy. A study performed by a group led by David Evans at the University of Alberta (PLoS Path., 2010) found that deletion of the vaccinia gene encoding the small subunit (R2, encoded by F4L) of the ribonucleotide reductase enzyme (a ubiquitous enzyme necessary for the generation of nucleotides to facilitate DNA synthesis) attenuated virus growth ~15-50 fold in HeLa cells. However, pancreatic cancer cells, naturally expressing high levels of cellular R2, could support F4L-deleted vaccinia virus growth at levels comparable to that of wild-type vaccinia virus. Further studies from our lab have demonstrated that this efficacy of F4L-deleted vaccinia virus growth, as well as cytotoxicity, extends to both bladder cancer and breast cancer. Here, we look to assess the efficacy of F4L-deleted vaccinia viruses in glioma. With the many clinical trials currently underway for the use of oncolytic viruses, it is becoming increasingly apparent that oncolytic virotherapy will be most effective in combination with other therapeutic modalities. This holds especially true to gliomas, which are notoriously heterogeneous and difficult to treat. As such, we propose that combining our F4L-deleted vaccinia virus mutants with radiotherapy, which is a standard of care in nearly all cases of glioma, may provide improved therapeutic benefit. Our results showed that human GBM cell lines that had been exposed to ionizing radiation (IR) remained supportive of infection with our mutant vaccinia virus deleted in both F4L and the thymidine kinase gene J2R (ΔF4LΔJ2R VACV). We also saw upregulation of R2 and its p53-inducible form, p53R2, in irradiated U-87 MG xenografts. As our ΔF4LΔJ2R VACV is dependent on cellular R2 for dNTP synthesis, this suggests that cells exposed to IR may become more susceptible to mutant VACV infection. Furthermore, early animal studies combining image-guided radiation therapy (IGRT) with ΔF4LΔJ2R VACV treatment of U87 MG xenografts have suggested that there may be a survival benefit to treating gliomas with either ΔF4LΔJ2R VACV alone or with the combination of ΔF4LΔJ2R/IR, when compared to IR alone or to no treatment. Though still in early stages, these results indicate that ΔF4LΔJ2R VACV may be a promising alternative to TMZ in the treatment of gliomas, especially if used as an adjuvant to radiotherapy.

• Subjects / Keywords

  • Virotherapy
  • Radiation
  • Glioblastoma
  • Vaccinia
  • Oncolytic
  • Glioma
  • Oncolytic virus

• Graduation date

  Spring 2017

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3V98040J

• 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.