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Neoantigen Vaccination for Lynch Syndrome Immunoprevention

林奇综合征免疫预防的新抗原疫苗接种

基本信息

批准号：
10478171
负责人：
Steven M Lipkin
金额：
$ 78.03万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478171
关键词：
Affect American Antigens Appearance CD4 Positive T Lymphocytes Cancer Vaccines Clinical Trials Code Colon Colonic Adenoma Colorectal Colorectal Cancer Colorectal Neoplasms DNA DNA Sequence Epithelial Epithelial Cells Foundations Frameshift Mutation Frequencies Genes Genetic Diseases Germ-Line Mutation Goals Hereditary Nonpolyposis Colorectal Neoplasms Human Immune Immunity Immunize Immunologic Surveillance Immunoprevention MLH1 gene MSH2 gene Malignant Neoplasms Mismatch Repair Missense Mutation Mosaicism Mucous Membrane Mus Mutate Mutation Neoplasms Patients Penetrance Peptides Poly A Recurrence Role Safety System T-Lymphocyte Tamoxifen Testing Tumor Burden Vaccination Vaccine Clinical Trial Vaccines Viral Viral Vector Work adaptive immune response adaptive immunity adenoma base effector T cell efficacy evaluation efficacy testing exome sequencing gene repair immunogenic immunogenicity innovation insertion/deletion mutation insight mouse model neoantigen vaccination neoantigen vaccine neoantigens premalignant recombinant viral vector tool transcriptome tumor vaccination strategy vaccine strategy

项目摘要

Lynch syndrome (LS) is a genetic disease predisposing to colorectal cancer (CRC) that affects more than one million Americans. Germline mutations in DNA mismatch repair (MMR) genes, primarily MLH1 and MSH2, cause deficient DNA mismatch repair (dMMR) and LS. LS CRCs have exceptionally high numbers of small insertion/deletion frameshift and missense mutations. Elevated dMMR mutation rates cause some mutations to recurrently arise in tumors from different patients. For example, the human TGFβR2 gene has a poly(A) coding repeat, and the same “shared” frameshift mutation is recurrently identified in >60% of LS dMMR CRCs. Here, we will use state of the art tools to systematically delineate recurrent LS mouse and human pre-malignant neoantigens, test whether vaccination with frequently mutated “shared” immunogenic neoantigens reduces LS mouse CRC penetrance, and elucidate adaptive immune mechanisms for CRC immunoprevention. In Aim 1 we will comprehensively delineate frequently mutated recurrent neoantigens in Lynch syndrome mouse colorectal mucosa and adenomas. This will provide insights into pre-malignant colon dMMR immunoediting mechanisms, the timing and sequence of dMMR neoantigen appearance, and systematically delineate the most immunogenic recurrent shared dMMR neoantigen vaccine targets for LS mouse CRC immunoprevention. In Aim 2 we will test the hypothesis that recurrent neoantigen vaccination reduces mouse Lynch syndrome mismatch repair deficient epithelial cells in colon mucosa. This will give insights into the mechanism of dMMR colon mucosal immunoediting, and test the efficacy and safety of a dMMR recurrent neoantigen vaccine strategy using the earliest neoantigen mutations for LS immunoprevention. In Aim 3, we will test the hypothesis that recurrent neoantigen vaccination reduces mouse Lynch syndrome colorectal tumor burden. This will evaluate the efficacy and safety of a dMMR recurrent adenoma neoantigen vaccine strategy for Lynch syndrome immunoprevention and provide insights into the mechanisms of dMMR immunoediting. Finally, in Aim 4 we will systematically delineate Lynch syndrome patient adenoma recurrent neoantigens. This will delineate the most promising candidate recurrent neoantigens that can be used for LS patient tumor vaccine clinical trials and give insights into dMMR immunoediting mechanisms. Our overall goal is to develop effective, safe mechanism based neoantigen vaccination strategies for Lynch syndrome CRC immunoprevention.

林奇综合征 (LS) 是一种易患结直肠癌 (CRC) 的遗传性疾病，影响多个个体百万美国人。 DNA 错配修复 (MMR) 基因的种系突变，主要是 MLH1 和 MSH2，导致 DNA 错配修复 (dMMR) 缺陷和 LS。 LS CRC 具有异常大量的小插入/缺失移码和错义突变。 dMMR 突变率升高会导致某些突变不同患者的肿瘤中反复出现。例如，人类 TGFβR2 基因具有编码聚腺苷酸 (poly(A)) 重复，并且在 > 60% 的 LS dMMR CRC 中反复发现相同的“共享”移码突变。这里，我们将使用最先进的工具来系统地描述复发性 LS 小鼠和人类癌前病变新抗原，测试接种频繁突变的“共享”免疫原性新抗原是否会减少 LS 小鼠结直肠癌外显率，并阐明结直肠癌免疫预防的适应性免疫机制。目标 1 我们将全面描述林奇综合征小鼠中频繁突变的复发性新抗原结直肠粘膜和腺瘤。这将为癌前结肠 dMMR 免疫编辑提供见解机制、dMMR 新抗原出现的时间和顺序，并系统地描述用于 LS 小鼠 CRC 免疫预防的最具免疫原性的复发性共享 dMMR 新抗原疫苗靶标。在目标 2 中，我们将检验反复新抗原疫苗接种可减少小鼠林奇综合征的假设错配修复结肠粘膜中缺陷的上皮细胞。这将有助于深入了解 dMMR 的机制结肠粘膜免疫编辑，并测试 dMMR 复发性新抗原疫苗的有效性和安全性使用最早的新抗原突变进行 LS 免疫预防的策略。在目标 3 中，我们将检验假设反复接种新抗原疫苗可减少小鼠林奇综合征结直肠肿瘤负担。这将评估林奇 dMMR 复发性腺瘤新抗原疫苗策略的有效性和安全性综合征免疫预防并提供对 dMMR 免疫编辑机制的见解。最后，在目标 4 我们将系统地描述林奇综合征患者腺瘤复发的新抗原。这将确定可用于 LS 患者肿瘤疫苗的最有希望的候选复发性新抗原临床试验并深入了解 dMMR 免疫编辑机制。我们的总体目标是开发有效的、基于安全机制的林奇综合征 CRC 免疫预防新抗原疫苗接种策略。