All ETDs from UAB

Advisory Committee Chair

Richard J Whitley

Advisory Committee Members

Etty N Benveniste

George Y Gillespie

James M Markert

Selvarangan Ponnazhagan

Justin C Roth

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Gliomas are the most common and fatal malignancy of the adult central nervous system. The need for new therapeutic options is clear, as standard of care therapies only extend median survival 12-14 months beyond diagnosis. Conditionally replication-competent oncolytic herpes simplex type-1 viruses (oHSV) have emerged as promising therapeutics for treating malignant gliomas. However, two factors that contribute to the dismal prognosis of malignant gliomas, immunosuppression and invasive growth, are also thought to limit virotherapeutic efficacy. We examined these factors in tumor microenvironments to explore novel strategies to treat malignant gliomas with oHSV for improved therapeutic response. In a Phase 1b trial, tumor specimens from immunocompromised subjects treated with oHSV were analyzed using microarray and RNA-sequencing. Interestingly, subjects with immunosuppressive tumors also displayed upregulation of immune response genes predominantly associated with antiviral effector functions. Furthermore, we confirmed changes in immunosuppressive markers after oHSV treatment in tumor microenvironments. Manipulating the immune response of oHSV through timed drug treatments and next-generation viruses may promote an anti-tumor immune response induced from oHSV treatment. Next, we sought to improve oHSV delivery and viral spread to satellite lesions characteristic of invasive growth. Human mesenchymal stem cells (MSCs) were evaluated for their potential as oHSV carrier cells based on optimal cell loading that resulted in productive viral replication and minimal carrier cell toxicity. Tumor targeting and killing were investigated with oHSV-loaded MSCs, and glioma cell lines were screened for their ability to produce chemokines that attract MSCs. Although oHSV-loaded MSCs were capable of handing off virus to tumor cells in vivo, carrier cells displayed preferential migration to the ventricles of the brain. MSCs loaded with oHSV may offer a more selective method of targeting satellite lesions that possess a defined chemokine profile for enhanced MSC migration. If successful, this cell vehicle strategy for oncolytic virotherapy would provide a novel approach to treating disseminated malignant gliomas.

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