FURTHER DEVELOPMENT OF COLOVAC, A MULTI-ANTIGEN MULTI-PEPTIDE VACCINE, FOR COLON CANCER PREVENTION

在美国，结直肠癌(CRC)是男性和女性确诊的第三大常见癌症，也是导致癌症死亡的第二大原因。美国预防服务工作组建议从50岁开始对没有症状的成年人进行结直肠癌筛查，这些成年人的平均风险为CRC，并且没有已知的与CRC风险增加相关的已知遗传病的家族病史，如林奇综合征或家族性腺瘤性息肉病(FAP)。虽然有证据表明，结直肠癌筛查总体上带来了实质性的好处，但预计2019年将有145,600例新的结直肠癌病例和51,020例结直肠癌死亡病例。除了筛查和早期发现外，能够进一步降低结直肠癌风险的预防策略将是非常有益的，特别是在高危人群中。以前的一些研究表明，使用非类固醇抗炎药(NSAIDs)可以降低患癌症的风险，包括结直肠癌。然而，它们的长期使用可能会伴随着严重的副作用，如胃肠道出血。需要采取更安全、更有效的办法来持久、长期地预防儿童疾病。 针对癌前病变和癌组织中过表达的肿瘤相关抗原(TAA)的癌症疫苗可能会激发抗肿瘤免疫，在癌前细胞发展成全面癌症之前阻断肿瘤的形成过程并消除它们。各种癌症免疫治疗的最新进展清楚地表明，如果肿瘤相关的免疫抑制被取消，例如通过免疫检查点阻断，免疫系统可以建立有效的抗肿瘤免疫反应。可以想象，在癌症预防环境中，主动免疫TAA可能会更有效地诱导有效的抗肿瘤免疫，因为肿瘤衍生的免疫抑制机制在癌前病变中可能发挥的作用较小。如果能够建立长期的免疫记忆，这种癌症疫苗可以作为一种更安全、更有效的癌症预防方法。 开发有效的癌症预防疫苗最重要的步骤之一是抗原的选择。Disis和他的同事此前已经证明，多个HLAII类等位基因之间的高结合亲和力预测免疫原性人类表位。他们开发了一种评分系统，旨在识别具有最佳结合亲和力和跨多个II类等位基因的混杂的表位。使用评分算法，他们证明了从识别的目标蛋白的免疫原性热点中选择的多肽可以在癌症患者和健康志愿者中诱导强大的抗原特异性1型T细胞反应。在肿瘤发生的临床前模型中，这些多肽的免疫介导了抗肿瘤效应。他们通过消除候选多肽中的Th2表位进一步优化了表位选择过程，并证明了具有强大抗肿瘤活性的多肽疫苗可以激发高度强大的保护性免疫。 目前开发非病毒癌症预防性疫苗的方法集中在以已知致癌蛋白为靶点的策略上。然而，通过仔细分析在癌前和癌前组织中过度表达但在正常组织中不表达的基因，可能会发现新的、更广泛适用的预防性癌症疫苗的靶抗原。Disis等人。最近报道了CDC25B、COX2和EGFR三种TAA的高免疫原性Th1促进表位，所有这些表位在结直肠癌中都过度表达，并与不良的疾病结局相关。他们展示了这些精选的基于TAA多肽的疫苗，称为Colovac，在肠道肿瘤发生的临床前模型中，诱导了1型免疫并降低了肿瘤负担。另外，她的团队还证明了非类固醇抗炎药显著减少了息肉的形成，同时增加了ApcMin/+小鼠息肉中CD8+T细胞的数量。 这项研究基于HHSN261201500036I/HHSN26100004(https://projectreporter.nih.gov/project_info_details.cfm?aid=9360921)，任务单下进行的工作，该工作重点是在肠道肿瘤发生的临床前模型中确定Colovac和NAPROXen联合方案的免疫协同作用和抗肿瘤活性。目前的研究旨在进一步推动Colovac疫苗走向临床应用。

Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women, and the second leading cause of cancer death in the US. The US Preventive Services Task Force recommends screening for colorectal cancer starting at age 50 years and continuing until 75 years of age for asymptomatic adults with average risk of CRC and without a family history of known genetic disorders associated with an increased risk of CRC such as Lynch syndrome or familial adenomatous polyposis (FAP). While the evidence supports that CRC-screening confers a substantial benefit overall, there will be an estimated 145,600 new CRC cases and 51,020 deaths from CRC expected in 2019. In addition to screening and early detection, prevention strategies that can further reduce the CRC risk will be of great benefit, in particular in high risk populations. A number of previous studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancers, including CRC. However, their extended use can be associated with serious side effects, such as gastrointestinal bleeding. Safer and more efficacious approaches are needed for durable long-term CRC prevention. Cancer vaccines targeting tumor-associated antigens (TAA) overexpressed in pre-cancerous and cancerous lesions may elicit antitumor immunity that intercepts tumorigenic process and eliminates precancerous cells before they progress to form a full-blown cancer. Recent advances in immunotherapies for various cancers have clearly shown that the immune system can mount effective antitumor immune responses if tumor-associated immunosuppression is abrogated, for example, by immune checkpoint blockade. It is conceivable that effective antitumor immunity may be more efficiently elicited by active immunization against TAA in the cancer prevention setting, as tumor-derived immunosuppressive mechanisms may play a lesser role in premalignant lesions. If long-term immunological memory can be established, such cancer vaccines can serve as a safer and more effective approach to cancer prevention. One of the most important steps toward developing effective cancer preventive vaccines is the selection of the antigens. Disis and colleagues have previously shown that high binding affinity across multiple HLA class II alleles predicts immunogenic human epitopes. They developed a scoring system designed to identify epitopes with optimal binding affinity and promiscuity across multiple class II alleles. Using the scoring algorithms, they demonstrated that peptides selected from the identified immunogenic hotspots of the target protein could induce robust antigen-specific type 1 T cell response in cancer patients and healthy volunteers. Immunization with these peptides mediated an antitumor effect in preclinical models of tumorigenesis. They further optimized the epitope selection process by eliminating Th2-epitopes from candidate peptides and demonstrated that highly robust protective immunity could be elicited by a multi-peptide vaccine with potent antitumor activity. Current approaches to the development of preventive vaccines for non-viral cancers are centered on strategies to target known oncogenic proteins. However, novel and more broadly applicable promising target antigens for preventive cancer vaccines may be identified from careful analyses of genes that are overexpressed in premalignant and malignant tissues but not in normal tissues. Disis et al. have recently reported highly immunogenic Th1-promoting epitopes from three TAAs, CDC25B, COX2 and EGFR, all of which are overexpressed in CRC and associated with poor disease outcomes. They showed these selected TAA-peptide based vaccine, referred to as Colovac, induced type 1 immunity and decreased tumor burden in preclinical models of intestinal tumorigenesis. Separately, her group has also demonstrated that NSAIDs significantly reduced polyp formation while increasing the number of CD8+ T-cell infiltrates in polyps in ApcMin/+ mice. This study is based on the work performed under the Task Order HHSN261201500036I/ HHSN26100004 (https://projectreporter.nih.gov/project_info_details.cfm?aid=9360921), which focused on determining immunologic synergy and antitumor activity of the combination regimen of Colovac and naproxen in preclinical models of intestinal tumorigenesis. The current study aims to further advance the Colovac vaccine towards clinical applications.