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:
- 金额:$ 105.28万
- 依托单位:
- 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:
- 关键词:Active ImmunizationAcuteAdenomatous Polyposis ColiAdultAdvisory CommitteesAffinityAgeAge-YearsAlgorithmsAllelesAntigen TargetingAntigensApcMin/+ miceBindingCD8-Positive T-LymphocytesCancer CenterCancer EtiologyCancer PatientCancer VaccinesCancerousCdc25B proteinCessation of lifeChronicClinical TrialsColorectal CancerDNA VaccinesDevelopmentDisease OutcomeEarly DiagnosisEpidermal Growth Factor ReceptorEpitopesFamily history ofFutureGastrointestinal HemorrhageGenesGenetic DiseasesGoalsHereditary Nonpolyposis Colorectal NeoplasmsHumanImmune systemImmunityImmunizationImmunologic MemoryImmunologicsImmunosuppressionImmunosuppressive AgentsImmunotherapyInterceptIntestinesLesionMalignant - descriptorMalignant NeoplasmsMediatingNaproxenNon-Steroidal Anti-Inflammatory AgentsNormal tissue morphologyOncogenicPTGS2 genePeptide VaccinesPeptidesPlayPolypsPre-Clinical ModelPremalignantPremalignant CellPrevention strategyPreventivePreventive servicePreventive vaccineProcessProteinsRegimenReportingRoleSystemT cell responseTissuesToxic effectTumor AntigensTumor BurdenTumor ImmunityTumor-DerivedVaccinesWomanWorkanti-tumor immune responseantitumor effectbasecancer diagnosiscancer preventioncancer riskclinical applicationcolon cancer preventioncolorectal cancer preventioncolorectal cancer riskcolorectal cancer screeningdesignhealthy volunteerhigh risk populationimmune checkpoint blockadeimmunogenicimmunogenicitymennoveloverexpressionpeptide based vaccinescreeningscreening guidelinesside effectsynergismtumortumorigenesistumorigenic
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)是美国男性和女性中第三大最常见的癌症,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,对于无症状、有平均结直肠癌风险且没有已知的与结直肠癌风险增加相关的遗传疾病家族史(如Lynch综合征或家族性腺瘤性息肉病(FAP))的成年人,从50岁开始进行结直肠癌筛查,一直持续到75岁。虽然有证据支持CRC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CRC病例和51,020例死于CRC。除了筛查和早期发现外,可以进一步降低结直肠癌风险的预防策略将大有裨益,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(NSAIDs)可以降低癌症的风险,包括结直肠癌。然而,它们的长期使用可能伴随着严重的副作用,如胃肠道出血。需要更安全、更有效的方法来长期预防结直肠癌。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CLINTON GRUBBS其他文献
CLINTON GRUBBS的其他文献
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{{ truncateString('CLINTON GRUBBS', 18)}}的其他基金
TASK ORDER: EVALUATION OF TWO DIFFERENT CLASSES OF COMPOUNDS (STAT3 INHIBITORS AND SERMS) FOR THE PREVENTION OF URINARY BLADDER CANCER
任务顺序:评估两类不同类型的化合物(STAT3 抑制剂和 SERMS)预防膀胱癌的作用
- 批准号:
10020556 - 财政年份:2019
- 资助金额:
$ 105.28万 - 项目类别:
IGF::OT::IGF EVALUATION OF AGENTS/PROTOCOLS THAT INHIBIT TWO MAJOR PATHWAYS INVOLVED IN HUMAN URINARY BLADDER CANCER(PI3K, EGFR) AND PROTOCOLS TO REDUCE THEIR TOXICITY
IGF::OT::IGF 对抑制人类膀胱癌(PI3K、EGFR)两个主要途径的药物/方案的评估以及降低其毒性的方案
- 批准号:
9151999 - 财政年份:2015
- 资助金额:
$ 105.28万 - 项目类别:
HHSN261201200021I/HHSN26100007Preclinical In Vitro and In Vivo Development Assays for Cancer Preventative Reagent. Project Title: Effect of Bazedoxifene Either Alone or in Combination with an Aroma
HHSN261201200021I/HHSN26100007癌症预防试剂的临床前体外和体内开发测定。
- 批准号:
8945265 - 财政年份:2014
- 资助金额:
$ 105.28万 - 项目类别:
HHSN261201200020I/HHSN26100006 Title: Preclinical In Vitro And In Vivo Screening Assays For Cancer Preventative Reagent Development, Task Order Title: Evaluation on the Prevention by Actoplus/Met (Pi
HHSN261201200020I/HHSN26100006 标题:癌症预防试剂开发的临床前体外和体内筛选测定,任务顺序标题:Actoplus/Met 预防的评估 (Pi
- 批准号:
8945320 - 财政年份:2014
- 资助金额:
$ 105.28万 - 项目类别:
PRECLINICAL IN VITRO AND IN VIVO SCREENING ASSAYS FOR CANCER PREVENTIVE AGENT DE
癌症预防剂 DE 的临床前体外和体内筛选试验
- 批准号:
7543340 - 财政年份:2004
- 资助金额:
$ 105.28万 - 项目类别:
In vitro and In Vivo screening of chemopreventive agents
化学预防剂的体外和体内筛选
- 批准号:
7927589 - 财政年份:2004
- 资助金额:
$ 105.28万 - 项目类别:
In vitro and In Vivo screening of chemopreventive agents
化学预防剂的体外和体内筛选
- 批准号:
8339908 - 财政年份:2004
- 资助金额:
$ 105.28万 - 项目类别:
CHEMOPREVENTION OF MNU INDUCED MAMMARY TUMORS
MNU 诱发的乳腺肿瘤的化学预防
- 批准号:
3621974 - 财政年份:1992
- 资助金额:
$ 105.28万 - 项目类别:
CHEMOPREVENTION OF MNU-INDUCED MAMMARY TUMORS IN THE RAT
MNU 诱导的大鼠乳腺肿瘤的化学预防
- 批准号:
3621972 - 财政年份:1992
- 资助金额:
$ 105.28万 - 项目类别:
CHEMOPREVENTION OF MNU INDUCED MAMMARY TUMORS
MNU 诱发的乳腺肿瘤的化学预防
- 批准号:
3621973 - 财政年份:1992
- 资助金额:
$ 105.28万 - 项目类别:
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