Stimulating Neo-Antigen Specific T Cell Responses in Head and Neck Cancers
Stimulating Neo-Antigen Specific T Cell Responses in Head and Neck Cancers
批准号:
10461025
负责人:
Jorge Silvio Gutkind
金额:
$83.81万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-19 至 2024-08-31
关键词:
AddressAdoptive Cell TransfersAntigensAutologousAutologous Tumor-Infiltrating LymphocyteBioinformaticsCancer RemissionCell TherapyCellsCellular ImmunologyCessation of lifeClinicalClonalityCombination immunotherapyComplexDNA Sequence AlterationDiseaseDisease remissionEcosystemEngraftmentEpitope spreadingFrequenciesGene Expression ProfileHead and Neck CancerHead and Neck Squamous Cell CarcinomaHumanImmuneImmune responseImmune systemImmunotherapeutic agentLeadMalignant NeoplasmsMediatingMetadataMethodsModelingMolecular ImmunologyMusMutationNormal tissue morphologyOncogenesOutcomePatientsPeripheral Blood Mononuclear CellPhenotypePre-Clinical ModelRadiation therapyRadioimmunotherapyRoleSTING agonistsT cell responseT-LymphocyteTestingTobaccoTreatment EfficacyTumor BurdenTumor Cell LineTumor-Infiltrating LymphocytesUnited StatesVaccine TherapyVirus Integrationadaptive immune responseantigen-specific T cellsbasecancer cellcarcinogenesisexomehuman diseaseimmune checkpoint blockadeimprovedin vivomouse modelneoantigensnovelnovel therapeuticspatient derived xenograft modelpatient responsepersonalized approachpre-clinicalprogrammed cell death protein 1receptorresponsetooltranscriptome sequencingtranslational oncologytumortumor xenograft
中文摘要
摘要
新抗原 (NeoAg) 为指导患者的免疫反应提供了独特而强大的机会
专门针对癌细胞,同时避免对正常组织造成损害。其可靠识别方法
缺乏中度突变负荷的肿瘤,例如头颈鳞状细胞癌(HNSCC),
然而,利用人体材料来了解可能性的临床前实验平台也是如此
NeoAg 特异性 T 细胞根除既定肿瘤的障碍。与专注的人一起工作
以及在细胞和分子免疫学、生物信息学和转化方面具有专业知识的协作团队
肿瘤学方面,我们开发了一套新颖的工具和方法来解决复杂的肿瘤/免疫问题
以新的、深入的方式构建生态系统。其中包括烟草诱发的 HNSCC 的独特新模型
致癌作用概括了人类疾病的许多关键特征,包括基因表达模式
激活的癌基因,一个强大的新型组合生物信息学和功能分析平台的鉴定
这些肿瘤产生的 NeoAg 可以被宿主免疫系统识别,这是一种新的临床前模型
联合放射免疫疗法,通过该疗法可以诱导和维持 NeoAg 特异性反应
(Sharabi/Sharma),最后,在以下情况下肿瘤引起的无反应的新临床前模型
使用人类 HNSCC 患者来源的异种移植 (PDX) 肿瘤和患者匹配的过继细胞疗法
对已确定的 NeoAg 具有特异性的肿瘤浸润淋巴细胞 (TIL)。这些研究将共同解决
自体 NeoAg 特异性 T 细胞可以根除 HNSCC 肿瘤的假设并确定了关键
控制治疗效果的定量和定性参数。
英文摘要
Abstract
Neoantigens (NeoAg) offer a unique and powerful opportunity for directing a patient’s immune response
specifically to cancer cells while avoiding damage to normal tissues. Methods for their reliable identification in
tumors of moderate mutational burden such as head and neck squamous cell carcinoma (HNSCC) are lacking,
however, as are preclinical experimental platforms for utilizing human material to understand the possibilities
and impediments in enabling NeoAg-specific T cells to eradicate established tumors. Working with a focused
and collaborative team with expertise in cellular and molecular immunology, bioinformatics, and translational
oncology, we have developed a set of novel tools and approaches to address the complex tumor/immune
ecosystem in new and incisive ways. These include a unique new model of tobacco-induced HNSCC
carcinogenesis which recapitulates many key features of the human disease including gene expression patterns
of activated oncogenes, a powerful new combined bioinformatic and functional analysis platform the identification
of NeoAg by these tumors can be recognized by the host immune system, a novel preclinical model of
combination radio-immunotherapy through which NeoAg-specific responses can be induced and sustained
(Sharabi/Sharma), and finally, a new preclinical model of tumor-induced unresponsiveness in the setting of
adoptive cellular therapy using human HNSCC patient-derived xenograft (PDX) tumors and patient-matched
tumor-infiltrating lymphocytes (TIL) specific for an identified NeoAg. Together, these studies will address the
hypothesis that autologous NeoAg-specific T cells can eradicate HNSCC tumors as well as defining the key
quantitative and qualitative parameters governing therapeutic efficacy.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1002/jlb.5ri0220-603rr
发表时间:
2020-04
期刊:
Journal of leukocyte biology
影响因子:
5.5
作者:
[Brightman SE, Naradikian MS, Miller AM, Schoenberger SP]
通讯作者:
Schoenberger SP
Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer.
靶向肿瘤杂种组在TMB低的非小细胞肺癌中进行个性化疫苗接种。
DOI:
10.1136/jitc-2021-003821
发表时间:
2022-03
期刊:
Journal for immunotherapy of cancer
影响因子:
10.9
作者:
[McCann K, von Witzleben A, Thomas J, Wang C, Wood O, Singh D, Boukas K, Bendjama K, Silvestre N, Nielsen FC, Thomas G, Sanchez-Elsner T, Greenbaum J, Schoenberger S, Peters B, Vijayanand P, Savelyeva N, Ottensmeier C]
通讯作者:
Ottensmeier C
Signal Transduction by PI3K/mTOR
-
批准号:10182868
-
项目类别:
-
资助金额:$48.31万
-
财政年份:2021
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Signal Transduction by PI3K/mTOR
-
批准号:10578841
-
项目类别:
-
资助金额:$48.35万
-
财政年份:2021
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Signal Transduction by PI3K/mTOR
-
批准号:10366013
-
项目类别:
-
资助金额:$47.86万
-
财政年份:2021
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC
-
批准号:10536607
-
项目类别:
-
资助金额:$49.0万
-
财政年份:2019
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Multidisciplinary Educational Approach to Reducing Cancer Disparities
-
批准号:10683194
-
项目类别:
-
资助金额:$35.2万
-
财政年份:2019
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Multidisciplinary Educational Approach to Reducing Cancer Disparities
-
批准号:10246272
-
项目类别:
-
资助金额:$34.6万
-
财政年份:2019
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Multidisciplinary Educational Approach to Reducing Cancer Disparities
-
批准号:10002204
-
项目类别:
-
资助金额:$46.91万
-
财政年份:2019
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision Therapy
-
批准号:10439800
-
项目类别:
-
资助金额:$46.24万
-
财政年份:2018
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision Therapy
-
批准号:10214590
-
项目类别:
-
资助金额:$46.71万
-
财政年份:2018
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Stimulating Neo-Antigen Specific T Cell Responses in Head and Neck Cancers
-
批准号:10115173
-
项目类别:
-
资助金额:$36.6万
-
财政年份:2018
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision Therapy
-
批准号:9977696
-
项目类别:
-
资助金额:$46.59万
-
财政年份:2018
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision Therapy
-
批准号:9753204
-
项目类别:
-
资助金额:$46.55万
-
财政年份:2018
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Stimulating Neo-Antigen Specific T Cell Responses in Head and Neck Cancers
-
批准号:10237372
-
项目类别:
-
资助金额:$84.93万
-
财政年份:2018
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Targeting Signaling Vulnerabilities for Oral Cancer Prevention
-
批准号:10540202
-
项目类别:
-
资助金额:$47.51万
-
财政年份:2017
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Area C: Genome-wide identification and targeting of resistance to cancer therapy
-
批准号:9482962
-
项目类别:
-
资助金额:$21.62万
-
财政年份:2017
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Targeting Signaling Vulnerabilities for Oral Cancer Prevention
-
批准号:10647799
-
项目类别:
-
资助金额:$47.51万
-
财政年份:2017
-
负责人:Jorge Silvio Gutkind
-
依托单位:
MOLECULAR BASIS OF SQUAMOUS DIFFERENTIATION AND NEOPLASIA IN SKIN & ORAL TISSUES
-
批准号:6289712
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Molecular Mechanisms of Growth Control and Carcinogenesis
-
批准号:6104616
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:Jorge Silvio Gutkind
-
依托单位:
Oral Carcinogenesis
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批准号:8929672
-
项目类别:
-
资助金额:$180.53万
-
财政年份:--
-
负责人:Jorge Silvio Gutkind
-
依托单位:
ORAL CARCINOGENESIS
-
批准号:6161812
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项目类别:
-
资助金额:$0.0万
-
财政年份:--
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负责人:Jorge Silvio Gutkind
-
依托单位: