Date of Award

January 2019

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard L. Edelson

Second Advisor

Douglas J. Hanlon

Abstract

Extracorporeal Photochemotherapy (ECP) is an FDA-approved immunotherapy that has been treating cutaneous T cell lymphoma (CTCL) for over three decades. ECP’s antitumoral effect is a consequence of its generation of functional, physiologic, inflammatory monocyte-derived dendritic cells (MoDCs) and apoptotic, patient-derived tumor, which collectively, stimulate the adaptive immune system. Thus, in CTCL, ECP serves as a therapeutic dendritic cell vaccine against patient-specific neoantigens. This mechanism of action suggests ECP’s potential application to other solid tumors. We tested ECP’s applicability to head and neck squamous cell carcinoma (HNSCC) using a trackable antigen system involving the constitutively expressed HPV16 E7 oncoprotein. We hypothesized that ECP would successfully stimulate anti-epitope CD8 T cells, quantified by IFN-gamma ELISA, following processing and cross-presentation of HPV16 E7+ peptides and tumor cells by MoDCs. The trackable antigen system employed a commonly cited epitope, E7(11-19). E7+ short peptide and long peptide generated significant IFNg (p<0.0001) relative to the null control group. Tumor cell line SCC61 T+ (E7hi) demonstrated significantly elevated IFNg production relative to SCC61 T- (non-E7 expressing tumor), but only in the presence of platelets, plate-passage, and overnight incubation (p<0.0001). These results suggest an antigen-specific CD8 T cell response and reiterate critical ECP components that have previously been shown to facilitate immunogenic MoDC generation. Immunogenic MoDC phenotype was confirmed with flow cytometry of inflammatory surface markers and intracellular cytokines, all of which were generally upregulated following ECP. Overall, we have demonstrated a proof-of-principle for ECP’s therapeutic vaccination against HNSCC. This is particularly relevant because ECP offers unique synergistic potential with recently FDA-approved checkpoint inhibitors.

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This is an Open Access Thesis.

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