Treating recurrent HNSCC with radiation and dual TGF-Beta/PD-L1.
使用放射和双重 TGF-Beta/PD-L1 治疗复发性 HNSCC。
基本信息
- 批准号:10477461
- 负责人:
- 金额:$ 32.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAftercareAntibodiesAttenuatedBiopsyBlood CellsCCL4 geneCD8B1 geneCancer BiologyCatchment AreaCell DeathCellsCessation of lifeClinicalColoradoDNADNA DamageDNA RepairEpithelialEpithelial CellsFDA approvedFibrosisFutureGenesGrowthHead and Neck CancerHead and Neck Squamous Cell CarcinomaHumanHuman PapillomavirusITGAM geneImmuneImmunocompetentImmunosuppressionImmunosuppressive AgentsImmunotherapyIndividualInfiltrationInterferonsInvestigational TherapiesMediatingMedical OncologyMetastatic Neoplasm to the LungModelingMolecularMusMutant Strains MiceMyeloid CellsNeoplasm MetastasisNitroquinolinesNude MiceOralOral mucous membrane structureOutcomeOxidesPathway interactionsPatientsPhase Ib Clinical TrialPhase Ib TrialPrediction of Response to TherapyPrognosisRadiationRadiation OncologyRadiation therapyRecurrenceRegimenRelapseReportingResistanceSafetySamplingScienceSerumSignal TransductionSpecimenSystemic TherapyT cell receptor repertoire sequencingT-Cell ReceptorT-LymphocyteTestingTherapeuticTherapeutic InterventionTimeTobaccoToxic effectTransforming Growth Factor betaTransforming Growth FactorsTransplantationTumor AntigensTumor ImmunityTumor-Infiltrating Lymphocytesantitumor effectbiomarker-drivencandidate validationcell injurycell killinghead and neck cancer patientimmune activationin situ cancer vaccinein situ vaccinationinhibitormolecular markermouse modelneoantigensneoplastic cellnoveloral mucositispatient derived xenograft modelphase II trialpredictive markerprogrammed cell death ligand 1programmed cell death protein 1radiation effectradiation responserecruitresponsesmall moleculetargeted agenttherapeutic targettherapy outcometreatment responsetumortumor immunologytumor microenvironmentvaccine efficacyvaccine response
项目摘要
SUMMARY, Project 2
Radiation therapy (RT) is commonly used for locally recurrent head and neck squamous cell carcinoma
(HNSCCs), yet no standard concomitant systemic therapy exists, and RT resistance rates are high. Antibodies
against programmed death-1 (PD-1) are FDA approved for treating relapsed/recurrent HNSCCs, but the
response rate is low. RT induces anti-tumor immunity by causing DNA damage and tumor cell killing that release
neoantigens to trigger an “in situ tumor vaccine” and activation of STING (stimulator of IFN genes) for local and
systemic immune activation. Conversely, RT also induces transforming growth factor-β1 (TGFβ1), an immune
suppressor, and PD-L1, a ligand of PD-1. These RT effects make dual TGFβ/PD-L1 inhibition a rational
combination being tested in this project. We have reported that TGFβ1 is elevated in >60% of tobacco-associated
HNSCCs. TGFβ1-mediated DNA repair contributes to RT resistance. TGFβ1 also contributes to RT-induced
toxicity, e.g., oral mucositis and fibrosis. Using our mouse HNSCC models, we found that TGFβ/PD-L1 dual
inhibition eradicated SCCs better than anti-PD-L1 alone in tumors with high TGFβ1 levels and high numbers of
PD-L1+/CD11b+ cells. We also found that TGFβ inhibition reduced metastases in athymic mice correlated with
reduced CD11b+ myeloid cells. We hypothesize that in advanced HNSCCs, TGFβ/PD-L1 dual inhibition
enhances RT-induced in situ vaccination, reverses immune suppression, and overcome RT resistance
via T cell-dependent and -independent mechanisms. We will test this hypothesis with experimental
therapeutics, mechanistic studies and analyses of HNSCC patient specimens. Aim 1 will determine if TGFβ/PD-
L1 dual inhibition enhances RT-induced in situ vaccination and systemic immune activation in oral SCC mouse
models. Experimental therapeutics of RT plus TGFβ/PD-L1 dual inhibition will be performed using mouse SCC
lines transplanted orthotopically to syngeneic mice, and T-cell dependent anti-tumor mechanisms will be
analyzed at the cellular and molecular levels. Aim 2 will determine how RT regimens in combination with
TGFβ/PD-L1 inhibition target tumor epithelial death and myeloid cells in mouse and human HNSCC models. T
cell-independent therapeutic benefit of RT in combination with TGFβ/PD-L1 inhibition will be analyzed. Aim 3
will conduct a Phase Ib trial for RT with M7824 (TGFβ/PD-L1 bidirectional inhibitor) in locally recurrent and
oligometastatic HNSCC patients and identify cellular and molecular markers as therapeutic targets. By
performing the proposed studies, we aim to bring a therapeutic intervention in real time to simultaneously
enhance immunotherapy and reduce RT resistance in HNSCC patients with poor prognosis. Additionally,
identifying predictive markers to the proposed treatment will lead to a true biomarker-driven Phase II trial with
pre-selected patients.
项目二总结
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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Xiao-Jing Wang其他文献
Xiao-Jing Wang的其他文献
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{{ truncateString('Xiao-Jing Wang', 18)}}的其他基金
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10796340 - 财政年份:2022
- 资助金额:
$ 32.81万 - 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10594019 - 财政年份:2022
- 资助金额:
$ 32.81万 - 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10481521 - 财政年份:2022
- 资助金额:
$ 32.81万 - 项目类别:
Treating recurrent HNSCC with radiation and dual TGF-Beta/PD-L1.
使用放射和双重 TGF-Beta/PD-L1 治疗复发性 HNSCC。
- 批准号:
10704598 - 财政年份:2021
- 资助金额:
$ 32.81万 - 项目类别:
Treating recurrent HNSCC with radiation and dual TGF-Beta/PD-L1.
使用放射和双重 TGF-Beta/PD-L1 治疗复发性 HNSCC。
- 批准号:
10268846 - 财政年份:2021
- 资助金额:
$ 32.81万 - 项目类别:
Mechanisms of Breaking Indolence in Squamous Cell Carcinoma
打破鳞状细胞癌惰性的机制
- 批准号:
9137250 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Mechanisms and Therapeutic Targets of SCC Metastasis
SCC转移的机制和治疗靶点
- 批准号:
10731726 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Mechanisms and Therapeutic Targets of SCC Metastasis
SCC转移的机制和治疗靶点
- 批准号:
10356069 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Testing Smad7-based biologics for treating chronic wounds
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- 批准号:
8779367 - 财政年份:2014
- 资助金额:
$ 32.81万 - 项目类别:
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