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Effects of entinostat and neoantigen vaccination on bladder cancer

恩替司他和新抗原疫苗接种对膀胱癌的影响

基本信息

批准号：
10751492
负责人：
Wolfgang Beckabir
金额：
$ 4.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751492
关键词：
Affect Antigens Automobile Driving Bioinformatics CD8-Positive T-Lymphocytes Cancer Model Cancer Patient Caring Cessation of life Clinical Trials Collaborations Computer software Development Epigenetic Process Flow Cytometry Funding Future Genetic Genitourinary system Genomics Growth HDAC1 gene Histone Deacetylase Inhibitor Human Immune checkpoint inhibitor Immunofluorescence Immunologic Immunologics Immunology In Vitro Knowledge Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Migration Assay Modeling Mus Oncology Patients Physicians Population Positioning Attribute Prognosis Regulatory T-Lymphocyte Research Sampling Scientist Single Nucleotide Polymorphism Source Specificity Stains Statistical Models Survival Rate T cell response T-Cell Immunologic Specificity T-Lymphocyte Testing Training Translational Research Tumor Antigens Tumor Biology Tumor Volume United States Work anti-PD-1 cancer diagnosis cancer immunobiology career effective therapy enzyme linked immunospot assay experience immune checkpoint blockade immunogenic immunogenicity improved in vivo men migration mouse model neoantigen vaccination neoantigens response single-cell RNA sequencing subcutaneous transcriptome sequencing transcriptomics treatment effect tumor tumor immunology tumor microenvironment ultrasound

项目摘要

Project Summary/Abstract Bladder cancer is a prevalent and deadly cancer, with over 80,000 new cases and 17,000 deaths annually in the United States. Advanced bladder cancer has only a 15% 5-year survival rate. One of the most effective treatments for advanced bladder cancer is immune checkpoint blockade (ICB), but only 20-30% of patients with advanced bladder cancer respond and most responses are not enduring. A promising new treatment identified by our group to improve bladder cancer ICB response is the selective class 1 histone deacetylase inhibitor entinostat. In a mouse model, entinostat plus anti-PD-1 (αPD-1) ICB induced complete, enduring responses in 67% of mice. Entinostat decreased intratumoral M-MDSC and Treg populations, decreased tumor single- nucleotide variant (SNV) neoantigen burden in vivo, increased expression of some SNV neoantigens in vitro, and increased T cell specificity for these neoantigens in vivo. However, much of the mechanism behind response to entinostat plus αPD-1 is unknown, particularly how entinostat decreases immunosuppressive populations and affects expression of the neoantigen landscape. Understanding this mechanism is important to predict which patients will respond and to potentially improve responses through antigen-directed therapy. We hypothesize that entinostat-induced ICB response is driven by increased M-MDSC differentiation, decreased M-MDSC migration, and increased expression of suppressed immunogenic neoantigens, augmenting response to neoantigen vaccination. I will investigate two components driving response to entinostat plus αPD-1: M-MDSCs and neoantigens. The training in computational and wet lab immunology, tumor biology and genetics, orthotopic murine tumor models, and translational research with a clinical trial, will assist me in becoming an independently funded physician-scientist leading a cancer immunology research lab and caring for bladder cancer patients. In our M-MDSC-focused Aim 1, I will perform flow cytometry and transwell migration assays with M-MDSCs from orthotopic bladder cancer model tumors to assess whether M-MDSC differentiation and migration are affected by entinostat treatment. I will conduct immunofluorescence staining of human tumors from the LCCC1827 entinostat window trial (NCT03978624) to assess whether adding entinostat to ICB treatment decreases M- MDSCs in humans. The Vincent Lab has developed LENS, a software platform to identify neoantigens from multiple genomic sources. In our neoantigen expression-focused Aim 2, I will use LENS to identify all the neoantigens in 3 murine bladder cancer lines developed by the Kim Lab, test T cell neoantigen specificity by high-throughput ELISPOT, and use statistical modeling to predict neoantigens immunogenicity. I will also validate whether entinostat-induced immunoediting occurs in human tumors from LCCC1827. In our neoantigen vaccination-focused Aim 3, I will test whether neoantigen vaccination improves tumor response to entinostat plus αPD-1. I will treat orthotopic tumors, measure their growth, and perform flow cytometry and single cell RNAseq to measure non-exhausted neoantigen-specific CD8+ T cell abundance.

项目总结/文摘