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：项目摘要/摘要 林奇综合征 (LS) 影响约 120 万美国人，并使他们易患结直肠癌 (CRC) 和其他癌症 LS正常细胞获得体细胞第二次突变并出现DNA错配修复缺陷。 (MMRD) MMRD 肿瘤具有极高数量的移码蛋白。 不同患者的肿瘤之间“共享”完全相同的复发突变。 例如，TGFBR2 具有 10bp 腺嘌呤重复序列，突变时会产生相同的移码蛋白 (FSP) 之前，我们发现 (a) 100% 的 MMRD CRC 患者具有 CD8+ T 细胞。 对 MMRD rFSP 具有反应性，(b) 进行的首次人体试验表明，肽疫苗接种效果良好 在晚期 MMRD 癌症患者中上调针对 rFSP 的 T 细胞免疫，并且 (c) 在功能上得到证实 在 LS 小鼠模型中，仅接种四种小鼠复发性新抗原即可增加 CD8+ 杀伤细胞和 CD4+ 辅助 T 细胞免疫反应，减轻 CRC 负担并延长无癌生存期。 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者，(a) 对最大数量的 LS 结直肠腺瘤进行了测序，并且 世界各地的腺癌，并确定了许多有前途的 MMRD 复发性新抗原候选疫苗， (b) 使用 MMRD CRC 细胞系、LS 患者结肠腺瘤衍生肿瘤和 NCI CPTAC 肿瘤图谱 确认复发性新抗原在肿瘤中真正表达为新肽，并且（c）表明 小鼠，脂质纳米颗粒 RNA (LNP-RNA) rFSP 疫苗接种的免疫原性明显高于肽疫苗 在这里，我们建议检验 LNP-RNA rFSP 疫苗接种引起 LS 小鼠的假设。 CD8+/CD4+ 免疫反应，减少肿瘤负荷，提高生存率 (AIM 1)，并描绘出最 该项目将鉴定出大多数免疫原性细胞毒性林奇综合征患者复发性新抗原（AIM 2）。 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 重要的是，我们的研究将为未来提供重要的机制见解。 几代有效的患者 LNP RNA 免疫预防疫苗。