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

• 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
• 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

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）是男性和女性中最致命的癌症之一。因为它通常在晚期被诊断出来，所以生存率极低。如果早期发现，例如，在边缘阴性PC或高度异型增生病变、胰腺上皮内瘤变（PanIN）和导管内乳头状粘液性肿瘤（IPMN）阶段，预计生存率将显著提高。然而，没有有效的筛查模式可以适用于一般人群。近年来，越来越多的共识是，一种特定的筛查和检测方法可以有益于一组遗传上易患PC的高危个体，包括BRCA 2基因突变、Lynch综合征、家族性非典型多发性痣黑色素瘤综合征（由p16/CDKN 2A突变引起）、Peutz-Jeghers综合征和Von Hippel-Lindau综合征。虽然对高危人群进行有针对性的筛查和监测可以早期发现浸润前胰腺病变，但目前尚不存在有效的干预方法来预防前驱病变进展为PC，除了手术切除，这是无法治愈的，并且可能与显著的发病风险相关。迫切需要采取安全和有效的预防措施，以减少与这一高度致命疾病有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具有突变激活的KRAS（例如G12 D）。KRAS突变是被认为驱动胰腺肿瘤发生的最早的遗传改变之一，并且经常在PanIN以及IPMN中检测到。已知参与早期肿瘤发生过程的突变的致癌驱动基因，如KRAS，是预防性干预的理想靶点。然而，目前没有靶向致癌KRAS的小分子药物可用于临床转化。靶向致癌KRAS的另一种方法可能是通过接种疫苗来增强宿主的免疫防御。对免疫调节机制以及先天性和适应性抗肿瘤免疫应答的特征的理解的最新进展揭示了宿主免疫系统对抗肿瘤生长的显著能力。当肿瘤源性免疫抑制被免疫检查点抑制剂阻断时，免疫系统可以释放更强大的抗肿瘤免疫应答，导致肿瘤清除。由宿主免疫系统靶向的肿瘤抗原（TA）的范围可以从肿瘤驱动癌蛋白、肿瘤相关突变体新抗原或肿瘤中过表达的自身抗原。很可能的是，如果TA特异性疫苗可以在致瘤过程之前或早期引发抗肿瘤免疫，宿主可能能够产生更强大的抗肿瘤免疫力，并保护自己免受新出现的恶性肿瘤的侵害，因为肿瘤相关的免疫抑制机制应该对宿主免疫功能的影响可以忽略不计。 在威斯康星州医学院的Ming You博士与DCP PREVENT项目合作进行的先前研究中，通过设计用于鉴定Th 1免疫促进表位的MHC II类结合算法选择的KRAS肽显示出高度免疫原性，以及用免疫原性KRAS肽的混合物进行疫苗接种（一种多肽KRAS疫苗）在诱导型突变KRAS驱动的肺肿瘤发生的基因工程小鼠模型中赋予显著的肿瘤预防作用。非常有可能的是，在其他KRAS驱动的肿瘤（如PC）中，使用已鉴定的多肽KRAS疫苗可能会获得类似的效果。鉴于人和小鼠KRAS之间的高度同源性，KRAS疫苗在预防性环境中具有很大的临床转化潜力。有许多临床前模型可用于测试KRAS疫苗的功效，包括基因工程小鼠模型。本研究基于根据任务指令HHSN 261201500037 I/HHSN 26100006（https：//www.example.com）进行的工作projectreporter.nih.gov/project_info_details.cfm? aid=9565898）。