DOI
https://doi.org/10.25772/KP8N-R750
Author ORCID Identifier
https://orcid.org/0000-0003-0746-7204
Defense Date
2021
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Xiang-Yang Wang Ph.D.
Second Advisor
John J. Ryan Ph.D.
Third Advisor
Andrew Poklepovic M.D.
Fourth Advisor
Devenand Sarkar Ph.D.
Fifth Advisor
Paula Bos Ph.D.
Sixth Advisor
Ross Mikkelsen Ph.D.
Abstract
Radiation therapy (RT) is one of the primary treatment modalities for head and neck squamous cell carcinoma (HNSCC). At the time of diagnosis two-thirds of HNSCC patients have local-advanced disease and 50-60% of these patients will experience a local-regional or metastatic relapse within three years. Improving the immunogenic response of RT may help address this clinical problem. However, current RT regimens have failed to reliably generate robust antitumor immunity as evidenced by the rarity of clinical abscopal responses. Recently we engineered a chimeric fusion molecule called Flagrp170, a novel immunostimulatory agent highly capable of promoting antigen presentation and T-cell activation. We hypothesize that the combination of RT and Flagrp170 provides superior immunogenic signals producing effective and durable antitumor immunity against HNSCC. We report that administration of Flagrp170 to the tumor sites upon RT using a small animal radiation research platform (SARPP) results in potent activation of antigen-presenting cells, increased functionality of tumor-infiltrating T-cells, and systemic immune augmentation. Additionally, the combination treatment is able to reduce the dose of RT required for tumor control and protects previously cured animals from subsequent tumor re-challenge. Finally, the combination treatment can successfully control the contralateral untreated tumors, supporting the superior activity of Flagrp170 in potentiating abscopal responses of RT. Our data suggest that the Flagrp170 may be used to enhance immunogenic cancer cell death in RT and resultant protective antitumor immunity can potentially help reduce post-RT recurrence of HNSCC.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-9-2021