All ETDs from UAB

Advisory Committee Chair

Richard J Whitley

Advisory Committee Members

George Y Gillespie

Paul A Goepfert

John C Kappes

Casey D Morrow

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malignant gliomas are the most frequently diagnosed and the most fatal primary brain tumors. Innovative therapeutic approaches are necessary to combat these devastating cancers, and oncolytic herpes simplex virus type-1 (oHSV) deleted of the γ134.5 neurovirulence gene is a promising adjunctive therapy. The primary mechanism of tumor clearance by oHSV is lytic replication specifically within malignant cells. oHSV also stimulates tumor infiltration of cytotoxic immune effector cells that can participate in tumor clearance. However, cytotoxic immune cells target oHSV as well as tumor, which may limit therapeutic efficacy. Further knowledge regarding the nature of these interactions and how the interactions reducing tumor burden may be enhanced will improve the utility of oHSV therapy. The studies described in this dissertation are based on the following hypotheses: 1) oHSV down-modulates a natural killer (NK) cell activating ligand (MHC class-I related chain A, MICA) from the surface of infected malignant glioma cells to evade immune detection, and 2) expression of the immunostimulatory cytokine interleukin-15 (IL-15) from oHSV stimulates cellular immune mediated clearance of aggressive brain tumors modeling malignant glioma. These studies 1) ascribe the ability of wild-type HSV-1 to down-modulate surface presentation of MICA to oHSV; 2) report the construction of an oHSV producing soluble murine (m)IL-15 in complex with the presenting mIL-15 receptor α (mIL-15Rα); 3) determine the oHSV-produced mIL-15/IL-15Rα complex is capable of stimulating NK cell proliferation and effector functions in vitro; and 4) determine the oHSV producing mIL-15/IL-15Rα does not improve survival in two models of aggressive brain tumors at the doses tested, but instead may stimulate NK cell mediated viral clearance. Taken together, these studies suggest that future efforts to improve oHSV efficacy for malignant glioma therapy should focus on preventing oHSV detection by NK cells while enhancing immune mediated tumor clearance.

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