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

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.

Transcriptional analysis highlights three distinct immune profiles of high-risk oral epithelial dysplasia

“…More recently, LOH in the chromosomal 9p arm involving the loss of JAK2 and PD-L1 was shown to affect immune responses in HNC and may promote immune evasion and foster the malignant transformation of OPMD (64). Hence, intervention to induce T cell infiltration or combination therapy targeting oncogenic genes involved in immunoediting may be a feasible approach to reactivate immune responses in the non-immune reactive subtype (65).…”

Safety and Immunogenicity of Combined DNA-Polyethylenimine and Oral Bacterial Idiotypic Vaccine for Patients with B-Cell Non-Hodgkin Lymphoma: A Pilot Study

“…Sequence encoding a secreted fusion of idiotype protein (scFv) and PVXCP was cloned into the pING vector. Vaccine construction incorporated the following components: a patient heavy chain leader peptide, VH-DH-JH fragment, linker L218 (GSTSGSGKPGSGEGSTKG) [ 16 ], light chain VL-DL-JL fragment, linker peptide AAAGPGP containing the NotI site [ 17 ], and the PVXCP sequence. The assembled plasmids were verified by restriction mapping and DNA sequencing.…”

Regulation of secretory pathway kinase or kinase-like proteins in human cancers

“…Recent research showed that a dual-antigenic peptide vaccine (PV1) derived from FJX1 and MAGED4B proteins induces antitumor immune responses in vitro ( 118 ). Increased infiltration of antigen-specific T cells into the tumor is induced by PV1, which is an important criterion for the success of immunotherapy and is associated with better patient prognosis ( 176 ). The cytotoxic cytokines, such as IFN-γ, granzyme B, and Th1, are secreted upon exposure to target cells which express the respective antigen post-PV1 stimulation and further inactivate a variety of oncogenic signaling pathways and induce the apoptosis of tumor cells ( 118 , 176 ).…”

“…Increased infiltration of antigen-specific T cells into the tumor is induced by PV1, which is an important criterion for the success of immunotherapy and is associated with better patient prognosis ( 176 ). The cytotoxic cytokines, such as IFN-γ, granzyme B, and Th1, are secreted upon exposure to target cells which express the respective antigen post-PV1 stimulation and further inactivate a variety of oncogenic signaling pathways and induce the apoptosis of tumor cells ( 118 , 176 ). PV1 inhibits tumor growth and significantly improves the prognosis when used alone or in combination with anti-PD1 ( 176 ).…”

“…The cytotoxic cytokines, such as IFN-γ, granzyme B, and Th1, are secreted upon exposure to target cells which express the respective antigen post-PV1 stimulation and further inactivate a variety of oncogenic signaling pathways and induce the apoptosis of tumor cells ( 118 , 176 ). PV1 inhibits tumor growth and significantly improves the prognosis when used alone or in combination with anti-PD1 ( 176 ). HNSCC patients are more responsive to PV1 stimulation, as it not only induces tumor-specific immune responses but also promotes the establishment of immunological memory.…”