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

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