Cancer Immune-Interception in a Spontaneous Non-Human Primate Model of Lynch Syndrome

自发性非人类灵长类动物林奇综合征模型中的癌症免疫拦截

基本信息

批准号：
10536878
负责人：
STANTON BRADLEY GRAY
金额：
$ 64.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2022-08-22 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536878
关键词：
Adaptive Immune System Adjuvant Adrenal Glands Affect Agonist American Animal Model Antigen-Presenting Cells Antigens Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Catalogs Cell Line Cells Chemopreventive Agent Clinical Chemoprevention Clinical Trials Coculture Techniques Code Colorectal Colorectal Cancer Combined Vaccines Coupled Cytotoxic T-Lymphocytes DNA Development Endometrium Enzyme-Linked Immunosorbent Assay Epithelial Cells Familial colorectal cancer Fostering Genes Genomics Germ-Line Mutation Goals Hereditary Nonpolyposis Colorectal Neoplasms Human Immune Immune system Immunologic Monitoring Immunologics In Vitro Incidence Industry Collaboration Intercept Knowledge Life MHC Class I Genes MLH1 gene Macaca mulatta Malignant Neoplasms Mass Spectrum Analysis Microsatellite Repeats Mismatch Repair Mission Modeling Mucous Membrane Naproxen Non-Steroidal Anti-Inflammatory Agents Normal Cell Outcome Ovary Patients Pattern Penetration Peptides Peripheral Blood Mononuclear Cell Permeability Phase Physiological Play Population Population Genetics Prevention Preventive vaccine Public Health Publishing Recurrence Reporting Research Rhesus Safety Small Intestines Stomach T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Toll-like receptors Translations United States National Institutes of Health Vaccination Vaccines Validation base bioinformatics pipeline cancer cell cancer prevention cancer type cell killing co-clinical trial cohort cytokine cytotoxic cytotoxic CD8 T cells cytotoxicity first-in-human gene repair high risk immune activation immune stimulant immunogenic immunogenicity innovation insertion/deletion mutation neoantigens next generation sequencing nonhuman primate novel response tool translation to humans tumor vaccine development vaccine platform

项目摘要

ABSTRACT Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC) affecting >1 million Americans. LS is caused by germline mutations in one of four DNA mismatch repair (MMR) genes. Normal colorectal epithelial cells in LS patients become MMR deficient after a somatic ‘second’ hit generating the accu- mulation of hundreds of insertion-deletion mutations (indels) in microsatellite sequences. These indels generate frameshift peptides (FSP) that become neoantigens (neoAg) and stimulate the adaptive immune system. We have previously reported that adaptive immune genes are highly expressed in LS pre-cancers, and we have generated a detailed neoAg catalog with >1,000 FSP neoAg from a cohort of LS pre-cancers and early-stage CRCs using next-generation sequencing tools coupled with a state-of-the-art bioinformatics pipeline. In addition, we have published the results of a phase Ib chemoprevention clinical trial in LS patients using naproxen showing immune-activation of colorectal mucosa resident cells. Taken together, these results point strongly towards the development of a vaccine for ‘recurrent’ and ‘shared’ LS-associated tumor neoAg combined with naproxen for pan-cancer prevention in the LS population. However, the main knowledge gap remains to select the most opti- mal neoAg peptides and to establish the efficacy and safety of the vaccination in a reliable animal model that allows immediate human translation. Rhesus macaques are a promising non-human primate (NHP) model dis- playing the closest genomic resemblance to humans. Our research team has reported the first colony of spon- taneous LS in rhesus carrying a germline mutation in MLH1. In addition, we are partnering with industry collab- orators in AMAL Therapeutics that have developed an innovative vaccination platform called KISIMA, integrating several selected FSP in tandem with a cell-permeable peptide fostering cell penetration, and a toll-like receptor agonist that acts as a self-adjuvant. Our central hypothesis is that our state-of-the-art bioinformatics pipeline for neoAg prediction will lead to the identification of the most immunogenic, recurrent across tumors, and shared among LS-associated tumor types FSP neoAg to be integrated in the KISIMA self-adjuvant vaccine platform, which will render a strong immunogenicity in combination with naproxen. To explore this hypothesis, we propose three specific aims: 1. To validate in vitro the immunogenicity of the top 150 recurrent neoAg shared by LS non-colorectal tumors using ELISpot, ELISA, and cytokine assays using PBMCs and CD8+ T cells from healthy human donors; 2. To develop artificial antigen-presenting cells (aAPC) expressing human LS neoAg to validate the cytotoxicity of neoAg-enriched T cells; and 3. To assess the immunogenicity of a neoAg combination using the novel self-adjuvant vaccine platform KISIMA alone and in combination with naproxen in a co-clinical trial in LS rhesus. The proposal is highly innovative because is developing a novel self-adjuavnt vaccine platform in a unique spontaneous NHP model of LS. The proposed research will significantly impact the field because it is a stepping stone to develop a Phase I first-in-human clinical trial to test a novel CRC vaccine for LS patients.

抽象的林奇综合征 (LS) 是遗传性结直肠癌 (CRC) 的最常见原因，影响超过 100 万人美国人，LS 是由四种 DNA 错配修复 (MMR) 基因之一的种系突变引起的。 LS 患者的结直肠上皮细胞在体细胞“第二次”打击产生准确的 MMR 后变得缺乏 MMR。微卫星序列中数百个插入缺失突变（indel）的合成。移码肽 (FSP) 成为新抗原 (neoAg) 并刺激适应性免疫系统。先前报道适应性免疫基因在LS癌前期高表达，我们有生成了一份详细的 neoAg 目录，其中包含来自 LS 癌前期和早期阶段队列的超过 1,000 个 FSP neoAg CRC 使用新一代测序工具以及最先进的生物信息学流程。我们已经发表了使用萘普生对 LS 患者进行 Ib 期化学预防临床试验的结果综上所述，这些结果强烈表明结直肠粘膜驻留细胞的免疫激活。开发一种针对“复发性”和“共享性”LS 相关肿瘤的疫苗 neoAg 与萘普生联合治疗然而，主要的知识差距仍然是选择最优化的方法。 mal neoAg 肽，并在可靠的动物模型中建立疫苗接种的有效性和安全性，恒河猴是一种有前途的非人类灵长类动物（NHP）模型。我们的研究小组报告了第一个与人类基因组最相似的群体。携带 MLH1 种系突变的恒河猴中的单一 LS 此外，我们正在与行业合作。 AMAL Therapeutics 的演说家开发了一个名为 KISIMA 的创新疫苗接种平台，将几种选定的 FSP 与促进细胞渗透的细胞渗透肽和 Toll 样受体串联作为自我佐剂的激动剂我们的中心假设是我们最先进的生物信息学管道。 NeoAg 预测将导致识别出最具免疫原性、跨肿瘤复发性和共享性的 LS 相关肿瘤类型 FSP neoAg 将被整合到 KISIMA 自身佐剂疫苗平台中，与萘普生联合使用会产生很强的免疫原性。为了探索这一假设，我们提出。三个具体目标： 1. 体外验证 LS 共享的前 150 个复发性新抗原的免疫原性使用 ELISpot、ELISA 和使用健康人的 PBMC 和 CD8+ T 细胞进行细胞因子测定来检测非结直肠肿瘤 2. 开发表达人类LS neoAg的人工抗原呈递细胞（aAPC）以进行验证富含 neoAg 的 T 细胞的细胞毒性；以及 3. 使用以下方法评估 neoAg 组合的免疫原性：新型自我佐剂疫苗平台 KISIMA 单独使用以及与萘普生联合使用在联合临床试验中 LS rhesus 的提案具有高度创新性，因为它正在开发一种新型的自我辅助疫苗平台。 LS 独特的自发 NHP 模型所提出的研究将对该领域产生重大影响，因为它是一个开发 I 期首次人体临床试验的垫脚石，以测试针对 LS 患者的新型 CRC 疫苗。