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

• 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
• 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

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）是男性和女性中诊断的第三大常见癌症，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，从50岁开始，持续到75岁，无症状的成年人具有平均CRC风险，并且没有与CRC风险增加相关的已知遗传性疾病家族史，如Lynch综合征或家族性腺瘤性息肉病（FAP）。虽然证据支持CRC筛查总体上带来了巨大的益处，但预计2019年将有145，600例新的CRC病例和51，020例CRC死亡。除了筛查和早期发现，可以进一步降低CRC风险的预防策略将非常有益，特别是在高危人群中。许多先前的研究表明，使用非甾体抗炎药（NSAID）可降低癌症（包括CRC）的风险。然而，它们的长期使用可能与严重的副作用有关，如胃肠道出血。需要更安全和更有效的方法来持久长期预防CRC。 靶向癌前病变和癌性病变中过表达的肿瘤相关抗原（TAA）的癌症疫苗可以引发抗肿瘤免疫，其阻断肿瘤发生过程并在癌前细胞进展形成完全发展的癌症之前消除癌前细胞。用于各种癌症的免疫疗法的最新进展已经清楚地表明，如果肿瘤相关的免疫抑制被消除，例如通过免疫检查点阻断，则免疫系统可以产生有效的抗肿瘤免疫应答。可以想象，在癌症预防环境中，通过针对TAA的主动免疫可以更有效地引发有效的抗肿瘤免疫，因为肿瘤源性免疫抑制机制在癌前病变中可能起较小的作用。如果能够建立长期免疫记忆，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的最重要步骤之一是抗原的选择。Disis及其同事先前已经表明，跨多个HLA II类等位基因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多个II类等位基因混杂性的表位。使用评分算法，他们证明了从靶蛋白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稳健的抗原特异性1型T细胞应答。免疫与这些肽介导的肿瘤发生的临床前模型中的抗肿瘤作用。他们通过从候选肽中消除Th 2-表位进一步优化了表位选择过程，并证明具有强效抗肿瘤活性的多肽疫苗可以引发高度稳健的保护性免疫。 目前开发非病毒性癌症预防性疫苗的方法集中在靶向已知致癌蛋白的策略上。然而，新的和更广泛适用的有前途的预防性癌症疫苗的靶抗原，可以确定从癌前和恶性组织中过表达，但在正常组织中的基因的仔细分析。Disis等人最近报道了来自三种TAA（CDC 25 B、COX 2和EGFR）的高度免疫原性Th 1促进表位，所有这些表位在CRC中过表达并与不良疾病结局相关。他们表明，这些选择的基于TAA肽的疫苗（称为Colovac）在肠道肿瘤发生的临床前模型中诱导1型免疫并降低肿瘤负荷。另外，她的小组还证明了NSAID显著减少了ApcMin/+小鼠息肉形成，同时增加了息肉中CD 8 + T细胞浸润的数量。 本研究基于根据任务指令HHSN 261201500036 I/HHSN 26100004（https：//www.example.com）进行的工作projectreporter.nih.gov/project_info_details.cfm? aid=9360921），其集中于确定Colovac和那洛维汀的组合方案在肠肿瘤发生的临床前模型中的免疫协同作用和抗肿瘤活性。目前的研究旨在进一步推进Colovac疫苗的临床应用。