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Dissertation
Effect of in situ immunization with vidutolimod in an oral leukoplakia model
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007597
Abstract
Leukoplakia is the most common premalignancy in the oral cavity, with the syndrome of white patches or spots forming inside the mouth. The risk factors include chronic irritation such as smoking, alcohol consumption, and chewing betel nuts. The majority of oral squamous cell carcinomas (OSCCs) arise from oral leukoplakia. However, leukoplakia is insufficiently researched and both diagnosing and treating oral leukoplakia are still problematic issues; with diagnosis being highly subjective and treatments (e.g., watchful waiting, conservative drug therapies, and surgical removal) possessing limited efficacy. There are no biomarkers specific for leukoplakia and the diagnosis of leukoplakia highly depends on the pathologist’s analysis of the collected biopsy, which can introduce a lot of variances. Thus, further understanding and an effective therapy for leukoplakia are still highly desirable to lower the risk of recurrence and malignant transformation to oral leukoplakia.
Human OSCC and leukoplakia samples were studied histologically and immunologically to reveal the local immune profile. Dendritic cells (DCs) are antigen-presenting cells that are crucial for stimulating CD8+/cytotoxic T cells to perform direct anti-tumor activities. Moderately-differentiated and well-differentiated OSCC were analyzed and compared with adjacent healthy tissue to reveal plasmacytoid DC (pDC) expression and activity. The distribution of a range of immune cells including DCs, CD4+ T cells, CD8+ T cells, macrophages, and B cells in different grades of oral leukoplakia was also investigated through spatial biology analysis.
Immune therapy is a promising approach to treating malignancies, however, its effect on the prevention and treatment of premalignancies has been rarely studied. This study focuses on the immune signature of leukoplakia and explores whether stimulating the immune system with an immune adjuvant, vidutolimod, can prevent the progression of oral leukoplakia or even cause disease regression. Vidutolimod comprises a bacteriophage Qβ protein shell encapsulating a Toll-like receptor (TLR)-9 agonist (G10). G10 is a potent activator of pDCs while also acting as a stimulator for B cells. However, the efficacy of G10 is limited when administered in a soluble/unprotected form due to its rapid degradation by DNases. The Qβ protein shell can protect G10 from degradation while also maximizing effective delivery to target TLR-9-expressing cells such as pDCs. After entering pDCs, vidutolimod induces IFN-α secretion, which may potentially promote cytotoxic T cells to kill premalignant cells. We expect that the boosted immune system after in situ vidutolimod injection could actively suppress malignancy progression.
To validate this hypothesis, a traditional murine model for inducing oral cancer was used to study leukoplakia development. Vidutolimod was administered with anti-PD1, an immune checkpoint inhibitor to achieve maximal immune response. The effect of treatment was analyzed histologically and immunologically. The immune profile will be revealed through analyzing immune cell populations in oral lesions, draining lymph nodes, and cytokine changes in serum before and after treatment.
Details
- Title: Subtitle
- Effect of in situ immunization with vidutolimod in an oral leukoplakia model
- Creators
- Yan Xu
- Contributors
- Aliasger K Salem (Advisor)Sean Geary (Committee Member)Nicole Brogden (Committee Member)Gary Milavetz (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy (Clinical Pharmaceutical Sciences)
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007597
- Publisher
- University of Iowa
- Number of pages
- xv, 53 pages
- Copyright
- Copyright 2024 Yan Xu
- Language
- English
- Date submitted
- 11/04/2024
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 49-53).
- Public Abstract (ETD)
- Leukoplakia is the most common premalignancy in the oral cavity, with the syndrome of white patches or spots forming inside the mouth. The majority of oral squamous cell carcinomas (OSCCs) arise from oral leukoplakia. However, leukoplakia is insufficiently researched and both diagnosing and treating oral leukoplakia are still problematic issues; with diagnosis being highly subjective and treatments (e.g., watchful waiting, conservative drug therapies and surgical removal) possessing limited efficacy. Thus, further understanding and an effective therapy for leukoplakia are highly desirable to lower the risk of recurrence and malignant transformation of oral leukoplakia. Immune therapy is a promising approach to treating malignancies. It facilitates our own immune system against cancer. However, its effect on the prevention and treatment of premalignancies has been rarely studied. This study focuses on the immune signature of leukoplakia and explores whether stimulating the immune system with an immune adjuvant, vidutolimod, can prevent disease progression. Vidutolimod comprises a virus protein shell encapsulating an immune stimulant. The virus protein shell can protect stimulant from degradation, thus maximizing effective delivery to specialized immune cells known as plasmacytoid dendritic cells (pDCs) which can present antigens, including cancer-specific antigens, to other immune cells such as cytotoxic T cells. After stimulating pDCs, vidutolimod induces specific cytokine secretion, which promotes cytotoxic T cells to kill premalignant cells. We expect that the boosted immune system after in situ vidutolimod injection could actively suppress malignancy progression. To validate this hypothesis, a traditional murine model for inducing oral cancer was used to study leukoplakia development. The effect of treatment was analyzed histologically and immunologically.
- Academic Unit
- Pharmacy; Craniofacial Anomalies Research Center
- Record Identifier
- 9984774549102771
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