Lung Cancer Vaccine

项目摘要 计算机胸部断层扫描（CT）肺癌筛查项目增加了对 癌前非实性（NS）结节，包含浸润前或微创腺癌。鉴于 NS结节可进展为浸润性腺癌（实性结节），拦截进展被认为是一种有效的治疗方法。 紧急临床优先然而，伴随疾病进展的细胞和分子改变是 不太了解。NS结节的HLA缺失率低于浸润性/转移性肺癌， 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结节中升高的活化T细胞。NS结节的整体基因组分析 鉴定了高肿瘤相关抗原（TAA）XAGE-1b和几种HLA限制性新抗原。这些 这些发现导致了一种假设，即针对NS结节相关抗原和/或 新抗原可以驱动T辅助细胞和细胞毒性CD 8 + T细胞的活化，同时减少肿瘤浸润性T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。目的1将确定脂质纳米粒的潜力 RNA（LNP RNA）XAGE-1b疫苗接种在临床前同基因模型中阻断NS结节进展 NSCLC。一种最先进的LNP-XAGE-1b RNA疫苗将与 LNP-RNA共享资源设施。一种新的生理学相关的小鼠模型， 将使用人NS结节的进展来确定XAGE-1b疫苗在拦截 NSN向浸润性癌的进展。LNP RNA疫苗免疫相关机制 将用全面的免疫分析方法阐明拦截。目标2将描绘最 在多种族队列中鉴定免疫原性和细胞毒性患者肺NS结节抗原和新抗原 临床标注的NS结节用于疫苗有效载荷。人类I类MHC（HLA）转基因小鼠将鉴定 体内免疫原性最强的肺NSN疫苗货物。患者特异性类肿瘤/自体T细胞共培养物 免疫肽组学将用于确认自体免疫细胞上的免疫原性和抗原呈递。 患者HLA。最后，研究NS结节患者新抗原特异性T细胞对自体免疫的细胞毒性潜力。 类肿瘤将用于对新抗原进行分级。 我们希望通过相关研究来描述最具免疫原性的疫苗， NCI PREVENT pre-IND疫苗开发和NCI CP-NET LS免疫预防临床试验，并提供 关键机制的见解，有效的病人LNP RNA免疫拦截疫苗。

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.