Lynch Vaccine

项目1：项目摘要/摘要 林奇综合征(LS)影响着约120万美国人，并使他们容易患上结直肠癌(CRC)和其他 恶性肿瘤。LS正常细胞获得体细胞二次突变并成为DNA错配修复缺陷 (MMRD)。MMRD肿瘤具有异常高数量的移码蛋白。MMRD突变率是这样的 提升了来自不同患者的肿瘤之间完全相同的重复突变。为 例如，TGFBR2有一个10bp腺嘌呤重复序列，当突变时，会导致相同的移码蛋白(FSP) 在约80%的MMRD癌中。此前，我们显示：(A)100%的MMRD CRC患者有CD8+T细胞 对MMRD rFSP具有反应性，(B)进行了第一次人体试验，表明多肽疫苗接种效果良好 上调晚期MMRD癌症患者对rFSP的T细胞免疫，以及(C)功能性 在LS小鼠模型中，仅接种四种小鼠复发新抗原可增加CD8+杀伤细胞和 CD4+辅助T细胞免疫反应，减轻CRC负担，延长无癌生存期。作为新的 初步数据，WE和CAP-IT CRI计算肿瘤免疫学核心(CTIC)Co-Pi Getz，一个初级 NCI肿瘤基因组图谱的设计者，已经(A)对最大数量的LS结直肠腺瘤进行了测序，并 并确定了许多有希望的MMRD复发新抗原候选疫苗， (B)使用MMRD CRC细胞系、LS患者结肠腺瘤来源的肿瘤样物和NCI CPTAC肿瘤图谱 以确认复发的新抗原在肿瘤中确实以新多肽的形式表达，以及(C)表明在 小鼠，脂纳米RNA(LNP-RNA)rFSP疫苗的免疫原性明显高于多肽 接种疫苗。在这里，我们建议检验LNP-RNA rFSP疫苗接种LS小鼠的假设 CD8+/CD4+免疫反应，减轻肿瘤负担，提高生存率(目标1)，并勾勒出最 免疫原性细胞毒性林奇综合征患者复发新抗原(AIM 2)。该项目将确定最多 NCI免疫原性复发新抗原预防前IND疫苗开发和NCI CP-Net LS 免疫预防临床试验。重要的是，我们的研究将为未来提供重要的机械性见解。 几代有效的患者LNP RNA免疫预防疫苗。

Project 1: Project Summary/Abstract Lynch syndrome (LS) affects ~1.2 million Americans and predisposes them to colorectal cancer (CRC) and other malignancies. LS normal cells acquire somatic second mutations and become DNA mismatch repair deficient (MMRD). MMRD tumors have exceptionally high numbers of frameshift proteins. MMRD mutation rates are so elevated that precisely the same recurrent mutations are “shared” among tumors from different patients. For example, TGFBR2 has a 10bp adenine repeat that, when mutated, causes the identical frameshift protein (FSP) in ~80% of MMRD CRCs. Previously, we showed that (a) 100% of MMRD CRC patients have CD8+ T cells reactive against MMRD rFSPs, (b) performed first-in-human trials showing that peptide vaccination robustly upregulates T-cell immunity against rFSP in advanced MMRD cancer patients, and (c) demonstrated functionally in LS mouse models that vaccination with only four mouse recurrent neoantigens increases CD8+ killer and CD4+ helper T-cell immune response, reduces CRC burden and prolongs cancer-free survival. As new preliminary data, we and CAP-IT CRI Computational Tumor Immunology Core (CTIC) Co-PI Getz, a primary architect of NCI tumor genome atlases, have (a) sequenced the largest number of LS colorectal adenomas and adenocarcinomas worldwide and identified many promising MMRD recurrent neoantigen vaccine candidates, (b) used MMRD CRC cell lines, LS patient colon adenoma derived tumoroids and the NCI CPTAC tumor atlas to confirm that recurrent neoantigens are bona fide expressed as neo-peptides in tumors and (c) showed that in mice, lipo-nanoparticle RNA (LNP-RNA) rFSP vaccination is significantly more immunogenic than peptide vaccination. Here we propose to test the hypothesis that LNP-RNA rFSP vaccination elicits LS mouse CD8+/CD4+ immune response, reduces tumor burden, increases survival (AIM 1), and delineates the most immunogenic cytotoxic Lynch syndrome patient recurrent neoantigens (AIM 2). This project will identify the most immunogenic recurrent neoantigens for NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials. Importantly, our studies will provide vital mechanistic insights into future generations of effective patient LNP RNA immunoprevention vaccines.