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.

项目概要计算机胸部断层扫描 (CT) 肺癌筛查计划增加了以下疾病的检出率含有浸润前或微浸润腺癌的癌前非实性（NS）结节。鉴于 NS 结节可进展为侵袭性腺癌（实性结节），阻止进展被认为是紧急临床优先事项。然而，伴随疾病进展的细胞和分子改变是不太了解。 NS 结节的 HLA 缺失率低于侵袭性/转移性肺癌，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 结节中激活的 T reg 升高。 NS 结节的全局基因组分析鉴定出高肿瘤相关抗原 (TAA) XAGE-1b 和几种 HLA 限制性新抗原。这些研究结果得出这样的假设：针对 NS 结节相关抗原和/或基于 RNA 的疫苗接种新抗原可以驱动 T 辅助细胞和细胞毒性 CD8+ T 细胞的激活，同时减少肿瘤浸润性 Tregs 损害 NS 结节进展为侵袭性腺癌。我们将通过两个具体目标来检验这一假设。目标 1 将确定脂质纳米粒子的潜力 RNA (LNP RNA) XAGE-1b 疫苗接种可阻止临床前同基因模型中的 NS 结节进展非小细胞肺癌。最先进的 LNP-XAGE-1b RNA 疫苗将与以下公司合作制造和优化 LNP-RNA 共享资源设施。一种新的生理相关小鼠模型，概括了人类 NS 结节的进展将用于确定 XAGE-1b 疫苗拦截的功效 NSN 进展为浸润性癌。 LNP RNA 疫苗免疫相关机制将通过全面的免疫分析方法来阐明拦截。目标 2 将描绘出最在多种族队列中鉴定出免疫原性和细胞毒性患者肺 NS 结节抗原和新抗原用于疫苗有效负载的临床注释 NS 结节。人类 I 类 MHC (HLA) 转基因小鼠将识别体内最具免疫原性的肺 NSN 疫苗货物。患者特异性肿瘤样/自体 T 细胞共培养免疫肽组学将用于确认自体抗体的免疫原性和抗原呈递患者HLA。最后，NS 结节患者新抗原特异性 T 细胞针对自体异体的细胞毒性潜力类肿瘤将用于对新抗原进行排序。我们期望描绘出最具免疫原性的疫苗货物以及信息丰富的相关研究 NCI PREVENT pre-IND 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 免疫拦截疫苗的关键机制见解。