Lynch Vaccine

林奇疫苗

• 批准号: 10505678
• 负责人: Steven M Lipkin
• 金额: $ 44.11万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/10505678
• 关键词: Adenine; Affect; American; Amino Acids; Atlases; Autologous; Automobile Driving; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; Cancer Burden; Cancer Patient; Cells; Clinical; Clinical Trials; Colonic Adenoma; Colorectal Adenocarcinoma; Colorectal Adenoma; Colorectal Cancer; Correlative Study; Cytotoxic T-Lymphocytes; DNA; Data; Disease; Future Generations; Genomics; Hereditary Nonpolyposis Colorectal Neoplasms; Human; Immune checkpoint inhibitor; Immune response; Immunity; Immunologics; Immunoprevention; MHC Class I Genes; Malignant Neoplasms; Microsatellite Instability; Mismatch Repair; Mus; Mutate; Mutation; Normal Cell; Patients; Peptides; Proteins; RNA; RNA vaccination; Recurrence; Science; T-Lymphocyte; TGFBR2 gene; Technology; Testing; Transgenic Mice; Tumor Burden; Tumor-Infiltrating Lymphocytes; Vaccination; Vaccines; adenoma; cancer genome; colon cancer cell line; colon cancer patients; colorectal cancer risk; cytotoxic; first-in-human; gene repair; immune checkpoint; immunogenic; immunogenicity; in vivo; insertion/deletion mutation; insight; mouse model; nanoparticle; neoantigen vaccine; neoantigens; peptide vaccination; premalignant; repaired; tumor; tumor immunology; vaccine candidate; vaccine development

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.

项目1：项目概要/摘要 Lynch综合征（LS）影响约120万美国人，使他们容易患结直肠癌（CRC）和其他癌症。 恶性肿瘤LS正常细胞获得体细胞二次突变并成为DNA错配修复缺陷型 （MMRD）。MMRD肿瘤具有异常高数量的移码蛋白。MMRD突变率是如此之高， 升高，在不同患者的肿瘤之间“共享”完全相同的复发突变。为 例如，TGFBR 2有一个10 bp的腺嘌呤重复序列，当突变时，会导致相同的移码蛋白（FSP） 在约80%的MMRD CRC中。以前，我们发现（a）100%的MMRD CRC患者具有CD 8 + T细胞， （B）进行首次人体试验，显示肽疫苗接种强烈地 上调晚期MMRD癌症患者针对rFSP的T细胞免疫力，并且（c）在功能上证明 在LS小鼠模型中，仅用四种小鼠复发性新抗原接种增加了CD 8+杀伤细胞， CD 4+辅助性T细胞免疫应答，降低CRC负担和无结直肠癌生存率。随着新 初步数据，我们和CAP-IT CRI计算肿瘤免疫学核心（CTIC）Co-PI Getz， NCI肿瘤基因组图谱的设计师，（a）测序了最多的LS结直肠腺瘤， 并鉴定了许多有希望的MMRD复发性新抗原疫苗候选物， (b)使用MMRD CRC细胞系、LS患者结肠腺瘤衍生的类肿瘤和NCI CPTAC肿瘤图谱 以证实复发性新抗原在肿瘤中真实地表达为新肽，并且（c）显示在肿瘤中， 在小鼠中，脂质纳米颗粒RNA（LNP-RNA）rFSP疫苗接种的免疫原性显著高于肽 预防针在此，我们提出检验LNP-RNA rFSP疫苗接种可增强LS小鼠免疫力的假设。 CD 8 +/CD 4+免疫应答，减少肿瘤负荷，增加生存期（AIM 1），并描绘了最 免疫原性细胞毒性Lynch综合征患者复发性新抗原（AIM 2）。该项目将确定最 用于NCI PREVENT pre-IND疫苗开发和NCI CP-NET LS的免疫原性复发新抗原 免疫预防临床试验。重要的是，我们的研究将为未来的研究提供重要的机制见解。 几代有效的患者LNP RNA免疫预防疫苗。