Lung Cancer Vaccine

肺癌疫苗

基本信息

批准号：
10505679
负责人：
NASSER Khaled ALTORKI
金额：
$ 36.26万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10505679
关键词：
Adenocarcinoma Antigens Autologous Biopsy Cancer Model Cancer Vaccines Carcinoma Chest Clinical Clinical Trials Coculture Techniques Collaborations Computing Methodologies Correlative Study Cytotoxic T-Lymphocytes Data Detection Disease Progression Exhibits Female Frameshift Mutation Genomics Glass Goals Human Image Immune Immune Targeting Immune checkpoint inhibitor Immunogenetics Immunoprevention Immunosuppression Impairment Intercept Investigation Lesion Lung Lung Adenocarcinoma Lung Neoplasms Lung nodule MHC Class I Genes Major Histocompatibility Complex Malignant neoplasm of lung Methods Modeling Molecular Mus Mutation Mutation Detection Natural History Nodule Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Ovary Patients Peptides Phenotype Physiological Placenta Prevalence Prevention Process Proteins RNA RNA vaccine Regulatory T-Lymphocyte Resource Sharing Solid Solid Neoplasm Source T-Lymphocyte Testing Testis Transgenic Mice Tumor Antigens Tumor Immunity Uncertainty Vaccination Vaccines base biobank cancer immunotherapy checkpoint therapy cohort computerized computerized tools cytotoxic cytotoxic CD8 T cells density efficacy testing exome sequencing experience immune RNA immunogenic immunogenicity improved in vivo insertion/deletion mutation insight interest lipid nanoparticle lung cancer screening lung tumorigenesis minimally invasive mouse model multi-ethnic mutant nanoparticle neoantigen vaccination neoantigens neoplastic novel pre-clinical preclinical study premalignant prevent protein expression screening program success tomography transcriptomics tumor tumor exome tumor immunology tumor-immune system interactions vaccine candidate vaccine development vaccine efficacy vaccine evaluation

项目摘要

PROJECT SUMMARY Computerized chest tomography (CT) lung cancer screening programs have increased the detection of premalignant non-solid (NS) nodules that harbor preinvasive or minimally invasive adenocarcinoma. Given that NS nodules can progress to invasive adenocarcinoma (solid nodules), intercepting progression is considered an urgent clinical priority. However, the cellular and molecular alterations that accompany disease progression are poorly understood. NS nodules exhibit lower rates of HLA deletions than invasive/metastatic lung cancer, and our integrated clinical and preclinical investigations have recently uncovered T cell-enriched immune microenvironments, including elevated activated T regs in NS nodules. Global genomic analysis of NS nodules identified high tumor-associated antigen (TAA) XAGE-1b and several HLA-restricted neoantigens. These findings have led to the hypothesis that RNA-based vaccination against NS nodule-associated antigens and or neoantigens can drive activation of T helper and cytotoxic CD8+ T cells while reducing tumor-infiltrating Tregs to impair NS nodule progression to invasive adenocarcinoma. We will test this hypothesis through two Specific Aims. Aim 1 will determine the potential of lipo-nanoparticle RNA (LNP RNA) XAGE-1b vaccination in intercepting NS nodule progression in preclinical syngeneic models of NSCLC. A state-of-the-art LNP-XAGE-1b RNA vaccine will be manufactured and optimized in collaboration with the LNP-RNA shared resource facility. A novel physiologically relevant mouse model recapitulating the progression of human NS nodules will be used to determine the efficacy of the XAGE-1b vaccine in intercepting the progression of NSN to invasive carcinoma. Mechanisms associated with LNP RNA vaccine immune interception will be elucidated with comprehensive immune profiling approaches. Aim 2 will delineate the most immunogenic and cytotoxic patient lung NS nodule antigens and neoantigens identified in a multi-ethnic cohort of clinically annotated NS nodules for vaccine payloads. Human class I MHC (HLA) transgenic mice will identify the most immunogenic lung NSN vaccine cargo in vivo. Patient-specific tumoroid/autologous T-cell cocultures and immunopeptidomics will be used to confirm immunogenicity and antigenic presentation on autologous patient HLA. Finally, the cytotoxic potential of NS nodule patient neoantigen-specific T-cells against autologous tumoroids will be used to rank neoantigens. We expect to delineate the most immunogenic vaccine cargo together with informative correlative studies for NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials and provide critical mechanistic insights into effective patient LNP RNA immune interception vaccines.

项目摘要计算机化胸部断层扫描（CT）肺癌筛查计划增加了检测具有前侵入性或微创腺癌的非固定性（NS）结节。鉴于 NS结节可以发展为浸润性腺癌（固体结节），截断的进展被认为是紧急临床优先级。但是，伴随疾病进展的细胞和分子改变是理解不佳。 NS结节比浸润性/转移性肺癌的HLA缺失率较低，并且我们的综合临床和临床前研究最近发现了富含T细胞的免疫微环境，包括NS结节中升高的激活的T regs。 NS结节的全球基因组分析鉴定出高肿瘤相关的抗原（TAA）XAGE-1B和几种HLA限制的新抗原。这些发现导致了以下假设：基于RNA的疫苗接种与NS结节相关的抗原和OR 新抗原可以驱动T助手和细胞毒性CD8+ T细胞的激活，同时将肿瘤浸润的Treg降低至损害NS结节向浸润性腺癌的进展。我们将通过两个具体目标检验这一假设。 AIM 1将确定Lipo-Nanoparpicle的潜力 RNA（LNP RNA）XAGE-1B疫苗接种在拦截NS结节进程中 NSCLC。最先进的LNP-XAGE-1B RNA疫苗将与 LNP-RNA共享资源设施。一种新型的生理相关小鼠模型，概括了人NS结节的进展将用于确定Xage-1b疫苗拦截的功效 NSN向入侵癌的发展。与LNP RNA疫苗免疫相关的机制截距将通过全面的免疫分析方法阐明。 AIM 2将最多描绘免疫原性和细胞毒性患者肺NS结节抗原和新抗原在多族裔队列中鉴定用于疫苗有效载荷的临床注释的NS结节。人类I类MHC（HLA）转基因小鼠将识别体内最免疫原性的肺NSN疫苗货物。患者特异性瘤或自体T细胞共培养免疫肽学将用于确认自体的免疫原性和抗原表现患者HLA。最后，NS结节患者新抗原特异性T细胞对自体的细胞毒性潜力瘤形成将用于对新抗原进行排名。我们希望描述最免疫原性的疫苗货物以及信息丰富的相关研究 NCI预防疫苗前疫苗开发和NCI CP-NET LS免疫预防临床试验，并提供对有效患者LNP RNA免疫截距疫苗的关键机理洞察力。