Advisory Committee Chair
C Ryan Miller
Advisory Committee Members
Gregory K Friedman
Anita B Hjelmeland
Jianmei W Leavenworth
L Burt Nabors
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
This dissertation covers data from published and pre-published studies exploring challenges and opportunities in the treatment of malignant glioma with emphasis in glioblastoma and oncolytic immunovirotherapy with an oncolytic herpes simplex virus type 1 (HSV-1) designed to induce expression of IL-12, M002 (murine IL-12) and M032 (human IL-12).It starts with the report of a study that uncovered important racial and socioeconomic disparities experienced by patients with glioblastoma treated in Alabama. Notable results also include the unexpected finding of increased survival in African American patients with glioblastoma even after controlling for factors associated with survival and socioeconomic disparities. The implications of this finding are discussed. This is followed by three in-depth reviews are also included, providing essential background in oncolytic immunovirotherapy as well as unique advantages of using HSV- 1 as oncolytic virus model for brain tumors, in particular high-grade glioma with particular emphasis in glioblastoma. Effective treatment options are limited for patients diagnosed with malignant glioma, and outcomes remain very poor. Recurrence and progression rates are universal with a subsequent historical median overall survival (mOS) of 6.5 months. Preclinical data showed that a second-generation oncolytic herpes virus (oHSV) armed to induce IL- 12 expression was a more effective anti-glioma agent than the first-generation oHSV. Results from an ongoing phase I clinical trial in pet dogs with high-grade glioma are discussed. It also includes results from an open-label, dose-escalating phase I trial designed to determine the safety and tolerability of intratumoral injection of the M032 virus in patients with recurrent or progressive MG. Patients in this study underwent stereotactic placement of up to four intratumoral catheters in enhancing tumor. The following day, M032 (starting at a dose of 105 plaque-forming units, PFU) was infused over a period of 6 hours. The primary endpoint was to determine the safety and maximum tolerated dose. Dose elevations were made using a modified Continual Reassessment Method with 7 dosing cohorts. Secondary endpoints were (1) to determine a recommended dose level for subsequent trials and (2) to obtain biologic data to optimize future studies. Twenty-one patients with recurrent MG ages 19 to 71 received M032 (16 Males, 5 Females). Fourteen patients had IDH wild-type tumors, and eighteen had unmethylated
Recommended Citation
Estevez-Ordonez, Dagoberto, "Challenges and Opportunities in Glioblastoma and Immunovirotherapy with Oncolytic Herpes Simplex Virus Type 1" (2023). All ETDs from UAB. 3495.
https://digitalcommons.library.uab.edu/etd-collection/3495