Lung Cancer Vaccine

项目总结 计算机胸部断层扫描(CT)肺癌筛查计划增加了对 癌前非实性(NS)结节，含有侵袭前或微侵袭性腺癌。考虑到 NS结节可进展为侵袭性腺癌(实体结节)，截止性进展被认为是一种 紧急临床优先事项。然而，伴随疾病进展的细胞和分子变化是 人们对此知之甚少。与浸润性/转移性肺癌相比，NS结节的HLA缺失率更低。 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结节中活性T调节蛋白的升高。NS结节的全球基因组分析 鉴定出高肿瘤相关抗原(TAA)XAGE-1b和几种人类白细胞抗原限制性新抗原。这些 这些发现导致了一种假设，即基于RNA的针对NS结节相关抗原的疫苗和或 新抗原可促进辅助性T细胞和细胞毒性CD8+T细胞的激活，同时减少肿瘤浸润性树突状细胞 阻碍NS结节进展为浸润性腺癌。 我们将通过两个具体目标来检验这一假设。目标1将确定脂纳米粒的潜力 RNA(LNP RNA)XAGE-1b疫苗在临床前同基因小鼠模型中阻断NS结节进展的作用 非小细胞肺癌。将与以下机构合作制造和优化最先进的LNP-XAGE-1b RNA疫苗 LNP-RNA共享资源设施。一种新的与生理相关的小鼠模型 人类NS结节的进展将被用来确定XAGE-1b疫苗的拦截效果 NSN向浸润性癌的进展。LNP RNA疫苗免疫相关机制的研究 拦截将通过全面的免疫分析方法加以阐明。目标2将描绘出最多的 在多民族队列中发现的免疫原性和细胞毒性患者肺NS结节抗原和新抗原 临床注明的NS结节用于疫苗有效载荷。人类第I类MHC(人类白细胞抗原)转基因小鼠将识别 体内免疫原性最强的肺NSN疫苗货物。患者特异性肿瘤样细胞/自体T细胞共培养 免疫药剂学将用于确认自体的免疫原性和抗原呈递。 患者的人类白细胞抗原。最后，NS结节患者新抗原特异性T细胞对自体移植瘤的细胞毒作用 类肿瘤将被用来对新抗原进行排序。 我们期望勾勒出最具免疫原性的疫苗货船，以及提供信息的相关研究 NCI预防前IND疫苗开发和NCI CP-Net LS免疫预防临床试验 对有效的患者LNP RNA免疫拦截疫苗的关键机制洞察。

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.