Development of Novel Spontaneous HPV Cervicovaginal Carcinoma Models for Cancer Immunotherapy

用于癌症免疫治疗的新型自发性 HPV 宫颈阴道癌模型的开发

基本信息

批准号：
10374864
负责人：
TZYY-CHOOU WU
金额：
$ 57.12万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374864
关键词：
Antigens Antitumor Response Automobile Driving Biology C57BL/6 Mouse CD3 Antigens CD8-Positive T-Lymphocytes Cancer Model Carcinoma Cells Cervical Squamous Cell Carcinoma Cervix carcinoma Characteristics Clinic Clinical DNA Data Development Electroporation Gene Expression Generations Genes Genetic Genome Human Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papillomavirus 16 Immune Immune Evasion Immune Targeting Immune checkpoint inhibitor Immune response Immunity Immunocompetent Immunosuppression Immunotherapeutic agent Immunotherapy Infection Injections Intervention Kinetics Lesion Luciferases MHC Class I Genes Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Methodology Modeling Molecular Monitor Monoclonal Antibody HuM291 Morphology Mus Oncogenes Oncogenic Oncoproteins Performance Plasmids Population Process Proteins Reporter Genes Research Role Shapes Sleeping Beauty System T-Cell Depletion Testing Therapeutic Therapeutic Effect Time Transfection Transposase Treatment Efficacy Tumor Immunity Tumor Markers Vaccinated Vaccines anti-tumor immune response base biological research cancer imaging cancer immunotherapy cervicovaginal clinically relevant experience immunosuppressed improved inhibitor luminescence neoplastic cell novel overexpression patient population plasmid DNA pre-clinical preclinical study predict clinical outcome premalignant success targeted treatment therapeutic HPV vaccinations therapeutic vaccine treatment strategy tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenesis vaccination strategy vaccine candidate

Antigens Antitumor Response Automobile Driving Biology C57BL/6 Mouse CD3 Antigens CD8-Positive T-Lymphocytes Cancer Model Carcinoma Cells Cervical Squamous Cell Carcinoma Cervix carcinoma Characteristics Clinic Clinical DNA Data Development Electroporation Gene Expression Generations Genes Genetic Genome Human Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papillomavirus 16 Immune Immune Evasion Immune Targeting Immune checkpoint inhibitor Immune response Immunity Immunocompetent Immunosuppression Immunotherapeutic agent Immunotherapy Infection Injections Intervention Kinetics Lesion Luciferases MHC Class I Genes Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Methodology Modeling Molecular Monitor Monoclonal Antibody HuM291 Morphology Mus Oncogenes Oncogenic Oncoproteins Performance Plasmids Population Process Proteins Reporter Genes Research Role Shapes Sleeping Beauty System T-Cell Depletion Testing Therapeutic Therapeutic Effect Time Transfection Transposase Treatment Efficacy Tumor Immunity Tumor Markers Vaccinated Vaccines anti-tumor immune response base biological research cancer imaging cancer immunotherapy cervicovaginal clinically relevant experience immunosuppressed improved inhibitor luminescence neoplastic cell novel overexpression patient population plasmid DNA pre-clinical preclinical study predict clinical outcome premalignant success targeted treatment therapeutic HPV vaccinations therapeutic vaccine treatment strategy tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenesis vaccination strategy vaccine candidate

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项目摘要

PROJECT SUMMARY / ABSTRACT The identification of human papillomavirus (HPV) as a causative agent for a host of conditions, particularly cervical cancer, has led to the development of HPV-targeting therapeutics, including therapeutic HPV vaccines, for the treatment of HPV-associated malignancies. However, the potent efficacies demonstrated by the therapeutic HPV vaccine candidates in preclinical studies are often not reflected in clinical settings. This discrepancy is potentially due to the inability of existing preclinical HPV tumor models to fully replicate the biology of clinical HPV-associated cancers. We hypothesize that an ideal preclinical HPV tumor model should possess the following characteristics: 1) forms spontaneous, localized, HPV oncogenic proteins-expressing tumors; 2) displays carcinoma morphology; 3) possesses a locally immunosuppressive tumor microenvironment (TME) resembling that of clinical HPV+ tumors; 4) tumor formation should follow clinical progression starting from a precancerous to an invasive and metastatic state; 5) be applicable to different MHC class I backgrounds; and 6) the tumor-bearing mice should respond appropriately to immunotherapeutic strategies and generate anti-tumor immunity. Preliminary data: We developed a strategy for the generation of preclinical spontaneous HPV cervicovaginal carcinoma based on orthotopic injection of oncogenic plasmids encoding HPV16-E6, HPV16-E7, constitutively active Akt, luciferase reporter gene, and Sleeping Beauty Transposase (SB) into the cervicovaginal tract of mice with electroporation to enhance transfection efficiency. Subsequent expression of SB induces the integration of plasmid DNA into the genome of transfected cells, resulting in persistent oncogenes expression and spontaneous transformation of transfected cells. In a systemic immunosuppressed setting induced by short-term anti-CD3 administration, intracervicovaginal oncogenic plasmid transfection led to the spontaneous formation of HPV+ tumors with carcinoma characteristics. We propose to further optimize our model by incorporating immunosuppressive molecules that are often overexpressed in clinical cervical cancers into our spontaneous HPV cervicovaginal tumor model and eliminate the need of short-term CD3 depletion. Also, we will further utilize genetic outbred mice and HPV16 pseudovirion delivery of oncogenes for the generation of spontaneous tumors, thereby recapitulating the genetic diverse patient population and HPV16 infection-induced oncogene introduction. Furthermore, we will examine various treatment strategies, such as the combination of therapeutic HPV vaccination with inhibitors of immunosuppressive molecules, in overcoming the immunosuppressive TME for the generation of improved therapeutic antitumor responses. Impact: A novel preclinical HPV cervicovaginal cancer model that faithfully recapitulates the clinical situation would potentiate crucial immunotherapeutic and biological research for HPV- associated cancers, provide better predictions for clinical outcomes of HPV-specific immunotherapies, and permit testing of novel molecular interventions targeting immune suppressive genes.