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

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，所以生存率极低。如果早期发现，例如，在边缘阴性PC或高度发育不良病变、胰腺上皮内瘤变（PanIN）和导管内乳头状粘液瘤（IPMN）阶段，生存率有望显著提高。然而，目前还没有适用于普通人群的有效筛查方式。近年来，越来越多的人一致认为，一种特定的筛查和检测方法可以有利于选择一组遗传上易患PC的高危个体，包括BRCA2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/CDKN2A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胰腺浸润前病变，但目前还没有有效的介入方式来防止前驱病变进展为前列腺癌，除了手术切除外，手术切除不能治愈，而且有很大的发病风险。迫切需要安全有效的预防措施，以降低与这一高度致命疾病相关的发病率和死亡率。

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).