Luận văn Thạc sĩ The Application Of Extracorporeal Photochemotherapy To Head And Neck Squamous Cell Carcinoma

Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine January 2019 The Application Of Extracorporeal Photochemotherapy To Head And Neck Squamous Cell Carcinoma Alp Yurter Follow this and additional works at: https://elischolar.library.yale.edu/ymtdl Recommended Citation Yurter, Alp, "The Application Of Extracorporeal Photochemotherapy To Head And Neck Squamous Cell Carcinoma" (2019) Yale Medicine Thesis Digital Library 3544 https://elischolar.library.yale.edu/ymtdl/3544 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale For more information, please contact elischolar@yale.edu The Application of Extracorporeal Photochemotherapy to Head and Neck Squamous Cell Carcinoma A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine by Alp Yurter Graduating Class of 2019 TABLE OF CONTENTS INTRODUCTION ECP Discovery ECP’s Mechanism of Action ECP’s Evolution Potential Application to Head and Neck Squamous Cell Carcinoma STATEMENT OF PURPOSE Specific Aims Hypothesis MATERIALS AND METHODS HPV16 E7 Antigen Sources Peripheral Blood Mononuclear Cells (PBMCs) 10 CD8 T Cells 10 Transimmunization (TI) procedure 13 Cell Stimulation Readouts 15 Statistics 16 RESULTS 18 REP generates a large population of CD8 T cells with Desired TCR specificity 18 CD8 T cells release IFNg upon direct stimulation with SP 18 Co-culture of PBMC with E7 (11-20) CD8 T cells and E7 Ags results in non-specific IFNg production 18 Co-culture of PBMC with E7 (11-19) CD8 T cells and E7 Ags results in Ag-specific IFNg production 19 TI, platelets, and E7 Antigen sources induce a pro-inflammatory MoDC phenotype 21 PD-1 can be used as surrogate for T cell stimulation 22 DISCUSSION 23 Limitations and Future Directions 26 REFERENCES 27 FIGURES 31 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