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，因为它通常在晚期才被诊断出来，因此如果早期发现，例如在切缘阴性的 PC 阶段，生存率极低。或高度不典型增生病变、胰腺上皮内瘤变（PanIN）和导管内乳头状粘液性肿瘤（IPMN），生存率预计会显着提高，但是，没有有效的筛查方法可以应用于这些疾病。近年来，越来越多的人认为，特定的筛查和检测方法可能对遗传上易患 PC 的特定高危人群有益，包括 BRCA2 基因突变、林奇综合征、家族性非典型患者。多发性痣黑色素瘤综合征（由 p16/CDKN2A 突变引起）、Peutz-Jeghers 综合征和 Von Hippel-Lindau 综合征，而对高危个体进行有针对性的筛查和监测可以实现早期发现。对于浸润前的胰腺病变，目前不存在有效的介入方式来阻止前驱病变进展为 PC，除了手术切除之外，手术切除不是治愈性的，并且可能会带来显着的发病风险，因此迫切需要采取安全有效的预防措施。需要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，占所有病例的 85% 以上。已知超过 90% 的 PDAC 具有突变激活的 KRAS（例如，KRAS 突变是最早的遗传改变之一）。据信驱动胰腺肿瘤发生，并且经常在 PanIN 以及已知参与其中的突变致癌驱动基因（例如 KRAS）中检测到。然而，目前尚无针对致癌 KRAS 的小分子药物可用于临床转化。另一种针对致癌 KRAS 的方法可能是通过疫苗接种来增强宿主的免疫防御。免疫调节机制以及先天性和适应性抗肿瘤免疫反应的特征揭示了宿主免疫系统对抗肿瘤生长的卓越能力。当肿瘤源性抑制性免疫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反应，导致宿主免疫系统靶向的肿瘤抗原（TA）范围很可能包括肿瘤驱动癌蛋白、肿瘤相关突变新抗原或肿瘤中过度表达的自身抗原。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，那么宿主可能能够建立更强大的抗肿瘤免疫并保护自己免受新出现的恶性肿瘤的侵害，例如肿瘤相关的免疫抑制机制对宿主免疫功能的影响应该可以忽略不计。 威斯康星州医学院的 Ming You 博士与 DCP PREVENT 计划合作进行的一项研究显示，通过 MHC II 类结合算法选择的 KRAS 肽（旨在识别 Th1 免疫促进表位）具有高度免疫原性，并且免疫原性 KRAS 肽混合物（一种多肽 KRAS 疫苗）的疫苗接种在可诱导突变 KRAS 驱动的肺的基因工程小鼠模型中具有显着的肿瘤预防作用鉴于人类和小鼠 KRAS 之间的高度同源性，很可能使用已鉴定的多肽 KRAS 疫苗在其他 KRAS 驱动的肿瘤中获得类似的效果，因此 KRAS 疫苗具有巨大的潜力。预防性环境中的临床转化 有许多临床前模型可用于测试 KRAS 疫苗的功效，其中包括基因工程小鼠模型。 HHSN261201500037I/HHSN26100006 (https://projectreporter.nih.gov/project_info_details.cfm?aid=9565898)。