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

进一步开发用于预防结肠癌的多抗原多肽疫苗 COLOVAC

基本信息

批准号：
10021897
负责人：
CLINTON GRUBBS
金额：
$ 105.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021897
关键词：
Active Immunization Acute Adenomatous Polyposis Coli Adult Advisory Committees Affinity Age Age-Years Algorithms Alleles Antigen Targeting Antigens ApcMin/+ mice Binding CD8-Positive T-Lymphocytes Cancer Center Cancer Etiology Cancer Patient Cancer Vaccines Cancerous Cdc25B protein Cessation of life Chronic Clinical Trials Colorectal Cancer DNA Vaccines Development Disease Outcome Early Diagnosis Epidermal Growth Factor Receptor Epitopes Family history of Future Gastrointestinal Hemorrhage Genes Genetic Diseases Goals Hereditary Nonpolyposis Colorectal Neoplasms Human Immune system Immunity Immunization Immunologic Memory Immunologics Immunosuppression Immunosuppressive Agents Immunotherapy Intercept Intestines Lesion Malignant - descriptor Malignant Neoplasms Mediating Naproxen Non-Steroidal Anti-Inflammatory Agents Normal tissue morphology Oncogenic PTGS2 gene Peptide Vaccines Peptides Play Polyps Pre-Clinical Model Premalignant Premalignant Cell Prevention strategy Preventive Preventive service Preventive vaccine Process Proteins Regimen Reporting Role System T cell response Tissues Toxic effect Tumor Antigens Tumor Burden Tumor Immunity Tumor-Derived Vaccines Woman Work anti-tumor immune response antitumor effect base cancer diagnosis cancer prevention cancer risk clinical application colon cancer prevention colorectal cancer prevention colorectal cancer risk colorectal cancer screening design healthy volunteer high risk population immune checkpoint blockade immunogenic immunogenicity men novel overexpression peptide based vaccine screening screening guidelines side effect synergism tumor tumorigenesis tumorigenic

项目摘要

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.

结直肠癌（CRC）是男性和女性诊断出的第三大常见癌症，也是美国癌症死亡的第二大原因。美国预防服务工作组建议筛查结直肠癌的年龄从50岁开始，一直持续到75岁的无症状成年人，具有平均CRC风险并且没有已知遗传疾病的家族史，与CRC的风险增加有关，例如lynch综合征或家族性腺瘤polyposis（FAP）。虽然证据支持CRC筛查总体上有很大的收益，但估计将有145,600例新的CRC病例和51,020例CRC预期的死亡。除了筛查和早期检测外，还可以进一步降低CRC风险的预防策略将是很大的好处，特别是在高风险中。先前的许多研究表明，使用非甾体类抗炎药（NSAIDS）降低了包括CRC在内的癌症的风险。但是，它们的扩展使用可能与严重的副作用有关，例如胃肠道出血。耐用的长期CRC预防需要更安全，更有效的方法。针对肿瘤相关抗原（TAA）过表达的癌症疫苗可能会引起抗肿瘤免疫，从而拦截肿瘤过程并消除前癌细胞在形成成熟癌症之前消除前癌细胞。各种癌症的免疫疗法的最新进展清楚地表明，如果消除与肿瘤相关的免疫抑制，例如通过免疫检查点阻断，免疫系统可以安装有效的抗肿瘤免疫反应。可以想象，在癌症预防环境中，对TAA的主动免疫可以更有效地引起有效的抗肿瘤免疫力，因为肿瘤衍生的免疫抑制机制在预抗病变中的作用可能较小。如果可以建立长期的免疫记忆，则这种癌症疫苗可以作为一种更安全，更有效的预防癌症方法。开发有效癌症预防疫苗的最重要步骤之一是选择抗原。司法和同事先前已经表明，多个HLA II类等位基因的高结合亲和力预测免疫原性的人类表位。他们开发了一个评分系统，旨在识别多个II类等位基因的最佳结合亲和力和滥交的表位。使用评分算法，他们证明了从靶蛋白的鉴定出的免疫原性热点中选择的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。这些肽免疫在肿瘤发生临床前模型中介导了抗肿瘤作用。他们通过从候选肽中消除Th2 epitopes进一步优化了表位选择过程，并证明具有有效的抗肿瘤活性的多肽疫苗可以引起高度鲁棒的保护性免疫。目前，用于开发非病毒癌的预防性疫苗的方法集中在靶向已知的致癌蛋白的策略上。然而，可以通过仔细分析过表达过表达的预防性和恶性组织，但在正常组织中未表达新颖的预防性癌症疫苗的新颖和更广泛的有希望的靶抗原。 Cisis等。最近报道了来自三个TAA的CDC25B，COX2和EGFR的高度免疫原性促进表位，所有这些表位在CRC中过表达，并且与疾病不良的结果有关。他们展示了这些选择的基于TAA肽的疫苗，称为Colovac，诱导1型免疫力和减轻肠道肿瘤发生模型中的肿瘤负担。另外，她的小组还证明了NSAID显着降低了息肉的形成，同时增加了APCMIN/+小鼠息肉中CD8+ T细胞浸润的数量。这项研究基于根据任务顺序HHSN261201500036I/HHSN26100004（https://projectReporter.gov/project/project_info_details.cfms.cfms）的工作，该工作= 9360921），该活动的组合和安态的组合= 9360921）萘普生在肠道肿瘤发生的临床前模型中。当前的研究旨在将Colovac疫苗进一步推向临床应用。