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Lynch Vaccine

林奇疫苗

基本信息

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
项目类别：
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

项目摘要

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