Journal Article

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Wu, T.-C., Peng, Shiwen, Chang, Yung-Nien, Chi, Wei-Yu, Roden, Richard B. S., Huang, Chuan-Hsiang, Hung, Chien-Fu, Gaillard, Stephanie, Wang, Chenguang, Ferrall, Louise

2021

Overview

Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3′ to a signal sequence and 5′ to the HSP70 gene of Mycobacterium tuberculosis . Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8 + T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8 + T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation. IMPORTANCE Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. For patients with HPV16 + cervical intraepithelial neoplasia grade 2/3 (CIN2/3), the precursor of cervical cancer, intramuscular vaccination with a DNA vaccine targeting HPV16 E7 and then a recombinant vaccinia virus expressing HPV16/18 E6-E7 fusion proteins (TA-HPV) was safe, and half of the patients cleared their lesions in a small study (NCT00788164). Here, we sought to improve upon this therapeutic approach by developing a new DNA vaccine that targets E6 and E7 of HPV16 and HPV18 for administration prior to a TA-HPV booster vaccination and for application against cervical cancer in combination with a PD-1-blocking antibody.

• Publisher: American Society for Microbiology
• Subject: Animals / Antibodies, Monoclonal - administration & dosage / Antigens / Bacterial Proteins - genetics / Bacterial Proteins - immunology / Blocking antibodies / CD8 antigen / Cervical cancer / Clinical trials / Deoxyribonucleic acid / DNA / DNA vaccines / DNA-Binding Proteins - genetics / DNA-Binding Proteins - immunology / Female / Fusion protein / HSP70 Heat-Shock Proteins - genetics / HSP70 Heat-Shock Proteins - immunology / Hsp70 protein / Human papillomavirus / Human papillomavirus 16 - drug effects / Human papillomavirus 16 - genetics / Human papillomavirus 16 - immunology / Human papillomavirus 18 - drug effects / Human papillomavirus 18 - genetics / Human papillomavirus 18 - immunology / Humans / Immune checkpoint inhibitors / Immune response / Immune response (cell-mediated) / Immunization, Secondary - methods / Immunotherapy / Infections / Lymphocytes / Lymphocytes T / Malignancy / Mice / Mice, Inbred C57BL / Monoclonal antibodies / Nucleotide sequence / Oncogene Proteins, Viral - genetics / Oncogene Proteins, Viral - immunology / Optimization / Papillomavirus E7 Proteins - genetics / Papillomavirus E7 Proteins - immunology / Papillomavirus Infections - genetics / Papillomavirus Infections - immunology / Papillomavirus Infections - mortality / Papillomavirus Infections - prevention & control / Papillomavirus Vaccines - administration & dosage / Papillomavirus Vaccines - genetics / Papillomavirus Vaccines - immunology / PD-1 protein / Peptides / Plasmids / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Protein Engineering - methods / Proteins / Recombinant Fusion Proteins - administration & dosage / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - immunology / Repressor Proteins - genetics / Repressor Proteins - immunology / Research Article / Survival Analysis / Therapeutics and Prevention / Tuberculosis / Tumors / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - immunology / Uterine Cervical Neoplasms - mortality / Uterine Cervical Neoplasms - prevention & control / Vaccination - methods / Vaccines / Vaccines, DNA - administration & dosage / Vaccines, DNA - genetics / Vaccines, DNA - immunology / Vaccinia virus - chemistry / Vaccinia virus - immunology / Vectors (Biology)