TASK ORDER: FURTHER TESTING OF A MULTI-PEPTIDE KRAS VACCINE FOR PANCREATIC CANCER PREVENTION

任务顺序：进一步测试多肽 KRAS 疫苗预防胰腺癌的作用

基本信息

批准号：
10269104
负责人：
VENKATESHWAR CHINTHALAPALLY
金额：
$ 49.3万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-21 至 2021-08-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269104
关键词：
Algorithm Design Animals Antigen Targeting Autoantigens Automobile Driving BRCA2 Mutation Binding CDKN2A gene Characteristics Collaborations Consensus Detection Diagnosis Disease Early Diagnosis Epitopes Excision Familial Atypical Multiple Mole Melanoma General Population Genes Genetic Predisposition to Disease Genetically Engineered Mouse Goals Hereditary Nonpolyposis Colorectal Neoplasms Human Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunosuppression Individual KRAS2 gene Lesion MHC Class II Genes Malignant Neoplasms Malignant neoplasm of pancreas Modality Monitor Morbidity - disease rate Mucinous Neoplasm Mus Mutate Mutation Oncogenes Oncogenic Oncoproteins Operative Surgical Procedures Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Papillary Peptides Peutz-Jeghers Syndrome Pre-Clinical Model Preventive Preventive Intervention Preventive measure Process Reporting Risk Survival Rate Syndrome Testing Tumor Antigens Tumor Immunity Tumor-Derived Vaccinated Vaccination Vaccines Von Hippel-Lindau Syndrome Wisconsin Woman Work anti-tumor immune response base cancer prevention clinical translation effective intervention efficacy testing high risk immune function immunogenic improved lung tumorigenesis medical schools men mortality mutant neoantigens overexpression pancreatic cancer model pancreatic tumorigenesis prevent programs screening small molecule targeted agent tumor tumor growth tumorigenesis tumorigenic

项目摘要

Pancreatic cancer (PC) is one of the most lethal cancers in both men and women. Because it is usually diagnosed at an advanced stage, the survival rate is extremely poor. If detected early, for example, at the stage of margin-negative PC or high-grade dysplastic lesions, pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN), survival is expected to improve significantly. However, there are no effective screening modalities that can be applied to the general population. There has been an increasing consensus in recent years that a specific screening and detection approach can be beneficial to a select group of at-risk individuals who are genetically predisposed to PC, including those with BRCA2 gene mutations, Lynch syndrome, familial atypical multiple mole melanoma syndrome (caused by mutations in p16/CDKN2A), Peutz-Jeghers syndrome, and Von Hippel-Lindau syndrome. While targeted screening and monitoring of high-risk individuals chould allow early detection of pre-invasive pancreatic lesions, effective interventional modalities to prevent progression of precursor lesions to PC are currently non-existent, except for surgical resection, which is not curative and can be associated with a significant risk of morbidity. Safe and effective preventive measures are urgently needed to reduce morbidity and mortality associated with this highly deadly disease. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of PC and accounts for more than 85% of cases. More than 90% of PDAC are known to harbor mutationally activated KRAS (e.g. G12D). KRAS mutations are one of the earliest genetic alterations believed to drive pancreatic tumorigenesis and frequently detected in PanIN as well as in IPMN. Mutated oncogenic driver genes, such as KRAS, known to be involved in early tumorigenic process are ideal targets for preventive interventions. However, there are no small molecule agents targeting oncogenic KRAS presently available for clinical translation. Another approach to targeting oncogenic KRAS may be through boosting the host’s immune defense through vaccination. Recent advances in the understanding of immune regulatory mechanisms and the characteristics of innate and adaptive antitumor immune responses have uncovered the host immune system’s remarkable ability to counter tumor growth. When tumor-derived immune suppression is blocked by immune checkpoint inhibitors, the immune system can unleash more robust antitumor immune responses, leading to tumor clearance. Tumor antigens (TA) targeted by the host immune system can range from tumor-driving oncoproteins, tumor-associated mutant neo-antigens or self-antigens overexpressed in tumors. It is highly conceivable that if antitumor immunity can be elicited by TA-specific vaccines before or early in the tumorigenic process, the host may be able to mount more robust antitumor immunity and protect itself from emerging malignant tumors, as tumor-associated immunosuppressive mechanisms should have negligible effects on the host’s immune function. In a previous study carried out by Dr. Ming You from Medical College of Wisconsin in collaboration with the DCP PREVENT Program, KRAS peptides selected through MHC class-II binding algorithms, designed to identify Th1-immunity promoting epitopes, were shown to be highly immunogenic, and vaccination with a mixture of the immunogenic KRAS peptides (a multi-peptide KRAS vaccine) conferred significant tumor preventive effects in a genetically engineered mouse model of inducible mutant KRAS-driven lung tumorigenesis. It is highly conceivable that similar effects might be attained with the identified multi-peptide KRAS vaccine in other KRAS-driven tumors such as PC. Given the high degree of homology between human and mouse KRAS, the KRAS vaccine holds a great potential for clinical translation in a preventive setting. There are a number of preclinical models that can be used to test the efficacy of the KRAS vaccine including genetically engineered mouse models. This study is based on the work performed under the Task Order HHSN261201500037I/HHSN26100006 (https://projectreporter.nih.gov/project_info_details.cfm?aid=9565898).

胰腺癌（PC）是男性和女性最致命的癌症之一。由于通常在高级阶段被诊断出来，因此生存率极差。例如，如果在边缘阴性PC或高级发育不良病变，胰腺上皮内肿瘤（Panin）和导管内乳头状粘膜肿瘤（IPMN）的阶段，预计将有望显着改善。但是，没有有效的筛查方式可以应用于一般人群。近年来，人们达成了越来越多的共识，即特定的筛查和检测方法可能对一组特定的处于危险中的个体有益，这些个体通常偏爱PC，包括患有BRCA2基因突变的人，林奇综合征，家族性多种痣黑色素瘤综合征（由P16/CDKN2A中的突变引起，PETKN2A和PEEUTZ-JEGERSNDROME，pehorsyndrome andsndrome syndrome，综合征。尽管有针对性的筛查和监测高风险个体应允许早日检测到侵入性胰腺病变，但除了手术切除外，目前不存在预防前体病变到PC的有效介入方式，这是不现代的，这不是现代的，并且可能与严重的发病率相关。迫切需要采取安全有效的预防措施，以降低与这种高度致命疾病相关的发病率和死亡率。胰腺导管腺癌（PDAC）是最常见的PC类型，占病例的85％以上。已知超过90％的PDAC藏有突变活化的KRA（例如G12D）。 KRAS突变是最早的遗传改变之一，被认为驱动胰腺肿瘤发生并在Panin和IPMN中经常检测到。突变的致癌驱动基因（例如KRAS）已知参与早期肿瘤过程是预防性干预措施的理想目标。但是，目前没有针对致癌性KRA的小分子剂可用于临床翻译。靶向致癌性KRA的另一种方法可能是通过通过疫苗来增强宿主的免疫防御。了解免疫调节机制以及先天和适应性抗弱者免疫反应的特征的最新进展使宿主免疫系统具有明显的抵抗肿瘤生长的能力。当肿瘤衍生的免疫抑制被免疫切除点抑制剂阻塞时，可以通过免疫抑制剂阻断免疫抑制剂，免疫抑制剂可以释放免疫抑制作用，可以释放出更强大的稳健抗肿瘤免疫反应，从而导致肿瘤清除。由宿主免疫抑制系统靶向的肿瘤抗原（TA）范围从肿瘤驱动的癌蛋白，与肿瘤相关的突变体的新抗原或自我抗原在肿瘤中过表达。高度可以想象的是，如果在肿瘤过程之前或早期可以通过TA特异性疫苗引起抗肿瘤免疫力，则宿主可能能够实现更强大的抗肿瘤免疫学，并保护自身，并免受恶性肿瘤的侵害，因为肿瘤相关的免疫机制应该对宿主的免疫功能造成宿主的免疫功能。在先前由威斯康星州医学院与DCP预防计划合作的Ming You博士进行的研究中，Kras通过MHC II类结合算法选择了Petides，旨在识别促进表位的Th1免疫性的促进表位，并证明具有高度免疫原性的疫苗，并与Importim peterige peterection tumecine tumogine tumogine tumogine tumogine tumotic tumoties Peteries tumogine tumoties Peteries Peteries Peteries pectire（在诱导型KRAS驱动的肺肿瘤发生的一般工程小鼠模型中的影响。高度可以想象的是，在其他由KRAS驱动的肿瘤（例如PC）中鉴定出的多肽KRAS疫苗可能会产生类似的作用。鉴于人与小鼠KRAS之间的高度同源性，KRAS疫苗在预防性环境中具有巨大的临床翻译潜力。有许多临床前模型可用于测试KRAS疫苗的效率，包括一般工程的小鼠模型。这项研究基于任务订单HHSN261201500037I/HHSN26100006（https://projectReporter.nih.gov/project_info_details.cfm?aid=9565898）。