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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the
Chuan Wang1, Nur Syafinaz Zainal2, San Jiun Chai2
1Head and Neck Cancer Center, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
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 tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel 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 tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor 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 with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.
Insights
Novel DNA vaccines targeting MAGED4B and FJX1 antigens show promise for HPV-independent head and neck squamous cell carcinoma (HNSCC). These vaccines enhance T-cell infiltration and tumor control, improving outcomes alone and with checkpoint inhibitors.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- HPV-independent head and neck squamous cell carcinoma (HNSCC) has a low response rate (~16%) to anti-PD1 checkpoint inhibitors (CPIs).
- Tumor-infiltrating T cells (TILs) are critical for CPI effectiveness, making conversion of TIL-low to TIL-high tumors a key therapeutic goal.
Purpose of the Study:
- To develop and evaluate novel DNA vaccines to enhance T-cell infiltration and control tumor growth in HNSCC.
- To assess the immunogenicity of MAGED4B and FJX1 antigens in HNSCC patients and the efficacy of DNA vaccines targeting them, alone and in combination with CPIs.
Main Methods:
- Evaluated expression and immunogenicity of MAGED4B and FJX1 antigens in HNSCC patients.
- Utilized a syngeneic preclinical model to test DNA vaccines targeting these antigens, with and without anti-PD1 CPI.
- Assessed T-cell infiltration, tumor growth inhibition, and overall survival.
Main Results:
- MAGED4B and FJX1 were co-expressed in most HNSCC patients (43/44), with low pre-existing T-cell responses (0.06-0.12%).
- DNA vaccines induced antigen-specific T-cell responses and increased T-cell infiltration into tumors without affecting MDSCs or regulatory T cells.
- Vaccines alone and in combination with anti-PD1 significantly inhibited tumor growth, achieving tumor clearance in ~75% of mice.
Conclusions:
- MAGED4B and FJX1 are highly immunogenic antigens in HNSCC, suitable for therapeutic vaccination.
- DNA vaccines targeting these antigens induce robust T-cell responses, leading to significant tumor control, especially when combined with anti-PD1 therapy.
- This combination immunotherapy strategy offers a promising approach to benefit a broader population of HNSCC patients through antigen-specific immune activation.
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