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，对于具有平均 CRC 风险且没有与 CRC 风险增加相关的已知遗传性疾病（例如林奇综合征或家族性腺瘤性息肉病 (FAP)）相关的已知遗传性疾病家族史的无症状成年人，从 50 岁开始一直持续到 75 岁。虽然有证据表明结直肠癌筛查总体上具有显着效益，但预计 2019 年将有 145,600 例结直肠癌新病例和 51,020 例结直肠癌死亡病例。除了筛查和早期发现之外，可进一步降低结直肠癌风险的预防策略也将带来巨大益处，特别是对于高危人群。先前的许多研究表明，使用非甾体抗炎药 (NSAID) 可以降低患癌症（包括结直肠癌）的风险。然而，长期使用它们可能会导致严重的副作用，例如胃肠道出血。需要更安全、更有效的方法来持久预防结直肠癌。 针对癌前病变和癌性病变中过度表达的肿瘤相关抗原（TAA）的癌症疫苗可能会引发抗肿瘤免疫，从而拦截致瘤过程并在癌前细胞发展为成熟癌症之前消除它们。各种癌症免疫疗法的最新进展清楚地表明，如果通过免疫检查点阻断等方式消除肿瘤相关的免疫抑制，免疫系统可以产生有效的抗肿瘤免疫反应。可以想象，在癌症预防中，通过主动免疫TAA可能会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发挥较小的作用。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 及其同事此前已证明，多个 HLA II 类等位基因的高结合亲和力可预测免疫原性人类表位。他们开发了一种评分系统，旨在识别多个 II 类等位基因中具有最佳结合亲和力和混杂性的表位。使用评分算法，他们证明从目标蛋白的已识别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烈的抗原特异性 1 型 T 细胞反应。这些肽的免疫在肿瘤发生的临床前模型中介导了抗肿瘤作用。他们通过消除候选肽中的 Th2 表位来进一步优化表位选择过程，并证明具有有效抗肿瘤活性的多肽疫苗可以引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于针对已知致癌蛋白的策略。然而，通过仔细分析在癌前组织和恶性组织中过度表达但在正常组织中不过度表达的基因，可以鉴定出用于预防性癌症疫苗的新型且更广泛适用的有希望的靶抗原。迪西斯等人。最近报道了来自三种 TAA（CDC25B、COX2 和 EGFR）的高免疫原性 Th1 促进表位，所有这些表位在 CRC 中都过度表达，并与不良的疾病结果相关。他们展示了这些选定的基于 TAA 肽的疫苗（称为 Colovac）可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，她的团队还证明 NSAID 显着减少息肉形成，同时增加 ApcMin/+ 小鼠息肉中 CD8+ T 细胞浸润的数量。 本研究基于任务令 HHSN261201500036I/ HHSN26100004 (https://projectreporter.nih.gov/project_info_details.cfm?aid=9360921) 下进行的工作，重点是确定 Colovac 和 萘普生在肠道肿瘤发生的临床前模型中的应用。目前的研究旨在进一步推进 Colovac 疫苗的临床应用。