AUTHOR=Wang Chuan , Zainal Nur Syafinaz , Chai San Jiun , Dickie James , Gan Chai Phei , Zulaziz Natasha , Lye Bryan Kit Weng , Sutavani Ruhcha V. , Ottensmeier Christian H. , King Emma V. , Abraham Mannil Thomas , Ismail Siti Mazlipah binti , Lau Shin Hin , Kallarakkal Thomas George , Mun Kein Seong , Zain Rosnah binti , Abdul Rahman Zainal Ariff , Thomas Gareth J. , Cheong Sok Ching , Savelyeva Natalia , Lim Kue Peng 

TITLE=DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the Efficacy of Checkpoint Inhibitor

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.763086

DOI=10.3389/fimmu.2021.763086

ISSN=1664-3224

ABSTRACT=HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumour infiltrating T cells (TILs). Converting TILlow tumours to TILhigh tumours is thus critical to improve clinical outcome. Here we describe a novel DNA vaccine to facilitate the T-cell infiltration and control tumour growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting these two antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumour, but not MDSC and regulatory T cells. The vaccine inhibited tumour growth and improved the outcome alone and upon combination with anti-PD1 resulted in tumour clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and synergised with the anti-PD1 antibody conferring excellent tumour control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.