Author ORCID Identifier
0000-0002-0135-0817
Date of Graduation
5-2024
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Juan Fueyo, MD
Committee Member
Gheath Al-Atrash, DO, PhD
Committee Member
Wenbo Li, PhD
Committee Member
Bulent Ozpolat, MD, PhD
Committee Member
David Piwnica-Worms, MD, PhD
Committee Member
Ji Young Yoo, PhD
Abstract
Currently, there is no effective treatment for high-grade gliomas that are resistant to conventional treatments and immune checkpoint blockade therapies. Oncolytic viruses offer a new treatment modality by selectively replicating in cancer cells and inducing anti-tumor immunity. Among these viruses, the oncolytic adenovirus Delta-24-RGD has shown safety and efficacy in clinical trials for high-grade gliomas. Strategies to improve the efficacy of oncolytic virotherapy have aimed to heighten the immunogenicity of oncolytic viruses, either by incorporating immune-stimulating transgenes or by combining treatments with immune checkpoint blockades. However, such strategies may inadvertently trigger heightened immune responses to viral antigens, which may not always translate into increased responses against tumor antigens. Data from a clinical trial using Delta-24-RGD have revealed that the development of high titers of neutralizing antibodies against adenovirus serotype 5 can correlate with reduced patient survival. Moreover, analysis of tumor-infiltrating lymphocytes from another clinical trial using Delta-24-RGD revealed that patients developed dominant T-cell immune responses against viral antigens rather than tumor antigens. We hypothesized that protecting oncolytic adenoviruses from humoral and cellular immunity to viral antigens will enhance the effectiveness of virotherapy. Here, we utilized sera obtained from patients who underwent a completed clinical trial with Delta-24-RGD for recurrent malignant gliomas and observed the development of neutralizing antibodies following virus administration. Multiple injections of the virus increased the proportion of patients developing neutralizing antibodies. Additionally, we discovered that neutralizing antibodies limited the efficacy of Delta-24-RGD in an immunocompetent mouse model of glioma. Importantly, we developed a chimeric virus with hexon hypervariable regions from adenovirus serotype 43 that evaded neutralizing antibodies directed against adenovirus serotype 5. This chimeric virus demonstrated improved therapeutic efficacy in glioma-bearing mice with immunity against adenovirus serotype 5 compared to Delta-24-RGD. Furthermore, we identified dominant viral epitopes recognized by CD8+ T-cells against Delta-24-RGD and designed nanoliposomes encapsulating these epitopes. Injection of nanoliposomes induced cargo antigen-specific immune tolerance, thereby reducing anti-viral immune response. Reduced immune responses to viral antigens resulted in increased immune responses against tumor antigens, improving the therapeutic efficacy of oncolytic adenovirus. These two strategies demonstrate that protecting the therapeutic virus from various arms of the host immune system has the potential to significantly enhance the efficacy of oncolytic virotherapy, presenting a promising new treatment strategy for patients with high-grade gliomas.
Keywords
oncolytic virus, high-grade gliomas, immune response