Identification and assessment of unconventional tumor-associated antigens as potential targets for cytotoxic T-cell based immunotherapy of cancer
鉴定和评估非常规肿瘤相关抗原作为基于细胞毒性 T 细胞的癌症免疫疗法的潜在靶标
基本信息
- 批准号:10365225
- 负责人:
- 金额:$ 59.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:Antigen TargetingAntigensApplications GrantsBRAF geneBioinformaticsCancer PatientCategoriesCell surfaceCellular immunotherapyClinicalCytolysisCytotoxic T-LymphocytesDNADataDetectionDevelopmentDiseaseEngineeringEpitopesFoundationsGeneticGoalsHumanImmuneImmunotherapeutic agentImmunotherapyInfusion proceduresInterleukin-2InterventionIntronsKnowledgeLeukocytesLightMAP Kinase GeneMalignant NeoplasmsMass Spectrum AnalysisMediatingMelanoma CellMethodologyMethodsMinorityMitogen-Activated Protein KinasesNatureOncogenicPathway interactionsPatientsPeptide VaccinesPeptidesPhosphopeptidesPost-Translational Protein ProcessingProteomicsRNA EditingRNA SplicingRefractoryReportingResearchSafetySourceSpecificityT cell therapyT-Cell ReceptorT-LymphocyteTechniquesTherapeuticTranslatingTumor AntigensTumor-DerivedTumor-Infiltrating LymphocytesVaccinesWorkbasebioinformatics pipelinecancer immunotherapycancer therapycancer typecytotoxicdesigndriver mutationimmunogenicimmunogenicityinnovationmelanomamulticatalytic endopeptidase complexneoplastic cellnext generationnovelpersonalized immunotherapysuccesstherapeutic targettranscriptome sequencingtranscriptomicstumortumor infiltrating lymphocyte therapytumor specificity
项目摘要
PROJECT SUMMARY / ABSTRACT:
Cytotoxic T lymphocyte (CTL)-based immunotherapies have shown great success in the treatment of
patients with several different cancer types. CTLs recognize peptide antigens presented at the tumor cell
surface by HLA class I molecules, triggering specific tumor cell lysis. Defining the nature of such tumor-
associated antigens (TAAs) can directly facilitate therapeutic tumor targeting through a number of
interventions, including personalized vaccines, endogenous T cell infusion, or TCR-engineered
immunotherapies. However, only a minority of human TAAs can be confidently identified using conventional
proteomic methodologies. Recent evidence suggests this may be due to the fact that most of the
immunopeptidome is comprised of peptides derived from ‘non-canonical’ sources such as those derived
from translated introns, RNA editing, proteasome splicing, or containing post-translational modifications.
Although these represent potentially high value tumor targets, few of these have yet been validated as bona
fide TAAs. However, overcoming the challenges inherent in non-canonical TAA identification holds the
promise of significantly expanding the landscape of targetable antigens for cancer patients.
The specific objective of this project is to identify and assess non-canonical TAAs as potential
therapeutic targets for melanoma, as a necessary prerequisite and foundation for generating effective CTL-
based immunotherapies for treating patients with this disease. It is our central hypothesis that unique, non-
canonical TAAs can constitute shared immunotherapeutic CTL targets, and that those TAAs induced
downstream of oncogenic driver mutations such as BRAF(V600E) will show greater tumor specificity and
refractoriness to antigen loss. We have formulated this hypothesis based on preliminary data showing that
potentially targetable non-canonical TAA peptides can be identified using an integration of highly sensitive
mass spectrometry (MS) combined with genetic sequencing analysis and a novel, in-house bioinformatics
pipeline. We have also shown that constitutive oncogenic MAPK pathway activation leads to dramatic global
tumor immunopeptidome shifts that appear to potentially involve thousands of non-canonical TAAs. There is
a strong clinical rationale for this antigen discovery work since it will directly facilitate the development of
novel, CTL-based therapies with the potential to benefit large numbers of cancer patients.
The proposed work is innovative, because it will explore different categories of non-canonical TAAs
in cancer and assess their immunogenicity and potential therapeutic value as shared cancer targets. It will
also shed light on the transcriptomic and proteomic changes that occur upon oncogenic-mediated MAPK
pathway activation, and how this influences the tumor immunopeptidome. Lastly, fulfilling the outlined
objectives will have an important positive clinical impact, because they will facilitate development of the next
generation of novel antigen-specific CTL-based immunotherapies for melanoma patients, and possibly also
patients with other cancer types.
项目摘要/摘要:
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PATRICK HWU其他文献
PATRICK HWU的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('PATRICK HWU', 18)}}的其他基金
Identification and assessment of unconventional tumor-associated antigens as potential targets for cytotoxic T-cell based immunotherapy of cancer
鉴定和评估非常规肿瘤相关抗原作为基于细胞毒性 T 细胞的癌症免疫疗法的潜在靶标
- 批准号:
10655279 - 财政年份:2022
- 资助金额:
$ 59.67万 - 项目类别:
Biomarkers and Resistance Mechanisms in Melanoma T-cell Therapy
黑色素瘤 T 细胞治疗中的生物标志物和耐药机制
- 批准号:
8673758 - 财政年份:2014
- 资助金额:
$ 59.67万 - 项目类别:
Biomarkers and Resistance Mechanisms in Melanoma T-cell Therapy
黑色素瘤 T 细胞治疗中的生物标志物和耐药机制
- 批准号:
8935764 - 财政年份:2014
- 资助金额:
$ 59.67万 - 项目类别:
Biomarkers and Resistance Mechanisms in Melanoma T-cell Therapy
黑色素瘤 T 细胞治疗中的生物标志物和耐药机制
- 批准号:
9143058 - 财政年份:2014
- 资助金额:
$ 59.67万 - 项目类别:
DC Vaccination to Enhance Adoptive T Cell Transfer
DC 疫苗接种可增强过继性 T 细胞转移
- 批准号:
7910321 - 财政年份:2009
- 资助金额:
$ 59.67万 - 项目类别:
Activation of Plasmacytoid Dendritic Cells (pDCs) to Induce Antitumor Activity
激活浆细胞样树突状细胞 (pDC) 诱导抗肿瘤活性
- 批准号:
7685358 - 财政年份:2008
- 资助金额:
$ 59.67万 - 项目类别:
Activation of Plasmacytoid Dendritic Cells (pDCs) to Induce Antitumor Activity
激活浆细胞样树突状细胞 (pDC) 诱导抗肿瘤活性
- 批准号:
8245233 - 财政年份:2008
- 资助金额:
$ 59.67万 - 项目类别:
Activation of Plasmacytoid Dendritic Cells (pDCs) to Induce Antitumor Activity
激活浆细胞样树突状细胞 (pDC) 诱导抗肿瘤活性
- 批准号:
8133220 - 财政年份:2008
- 资助金额:
$ 59.67万 - 项目类别:
Activation of Plasmacytoid Dendritic Cells (pDCs) to Induce Antitumor Activity
激活浆细胞样树突状细胞 (pDC) 诱导抗肿瘤活性
- 批准号:
8135425 - 财政年份:2008
- 资助金额:
$ 59.67万 - 项目类别:
相似国自然基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
- 批准号:2022J011295
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
- 批准号:30801055
- 批准年份:2008
- 资助金额:19.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Bovine herpesvirus 4 as a vaccine platform for African swine fever virus antigens in pigs
牛疱疹病毒 4 作为猪非洲猪瘟病毒抗原的疫苗平台
- 批准号:
BB/Y006224/1 - 财政年份:2024
- 资助金额:
$ 59.67万 - 项目类别:
Research Grant
Uncovering tumor specific antigens and vulnerabilities in ETP-acute lymphoblastic leukemia
揭示 ETP-急性淋巴细胞白血病的肿瘤特异性抗原和脆弱性
- 批准号:
480030 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Operating Grants
A novel vaccine approach combining mosquito salivary antigens and viral antigens to protect against Zika, chikungunya and other arboviral infections.
一种结合蚊子唾液抗原和病毒抗原的新型疫苗方法,可预防寨卡病毒、基孔肯雅热和其他虫媒病毒感染。
- 批准号:
10083718 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Small Business Research Initiative
Regulation of B cell responses to vaccines by long-term retention of antigens in germinal centres
通过在生发中心长期保留抗原来调节 B 细胞对疫苗的反应
- 批准号:
MR/X009254/1 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Research Grant
Adaptive Discrimination of Risk of Antigens in Immune Memory Dynamics
免疫记忆动态中抗原风险的适应性辨别
- 批准号:
22KJ1758 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Grant-in-Aid for JSPS Fellows
22-ICRAD Call 2 - Improving the diagnosis of tuberculosis in domestic ruminants through the use of new antigens and test platforms
22-ICRAD 呼吁 2 - 通过使用新抗原和测试平台改善家养反刍动物结核病的诊断
- 批准号:
BB/Y000927/1 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Research Grant
Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella
经典和高毒力克雷伯氏菌的不同多糖抗原引发的保护性免疫
- 批准号:
10795212 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Integrative proteome analysis to harness humoral immune response against tumor antigens
综合蛋白质组分析利用针对肿瘤抗原的体液免疫反应
- 批准号:
23K18249 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
- 批准号:
10735075 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别:
Targeting T3SA proteins as protective antigens against Yersinia
将 T3SA 蛋白作为针对耶尔森氏菌的保护性抗原
- 批准号:
10645989 - 财政年份:2023
- 资助金额:
$ 59.67万 - 项目类别: