Image-guided TRAIL-enhanced CAR T-cell immunotherapy
Image-guided TRAIL-enhanced CAR T-cell immunotherapy
批准号:
10371094
负责人:
Vladimir Ponomarev
金额:
$56.56万
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:
2018-04-01 至 2023-03-31
关键词:
Adoptive ImmunotherapyAdverse effectsAffectAntigensApoptosisApoptoticBiologicalBreastCancer CenterCancer PatientCellsCellular immunotherapyCessation of lifeChemotherapy and/or radiationClinicClinical ResearchClinical TrialsColorectalComplementDisease remissionExhibitsFOLH1 geneGenesGenetic EngineeringGliomaGoalsHormonalImageImmuneImmune responseImmune systemImmunotherapeutic agentImmunotherapyLigandsLungMalignant NeoplasmsMalignant neoplasm of prostateMeasurableMeasurementMediatingMembraneModalityMonitorMusNormal CellPatientsPharmaceutical PreparationsPositron-Emission TomographyProcessProstateProtocols documentationRadiationRadiation therapyRadiopharmaceuticalsRecombinantsReporter GenesResistanceStimulusSurfaceT cell therapyT-Cell ActivationT-LymphocyteT-Lymphocyte and Natural Killer CellTNF geneTNFRSF10A geneTNFRSF10B geneTNFSF10 geneTestingTherapeuticTimeTranslatingTranslationsTumor ImmunityWorkXenograft Modelanti-PSMAantigen-specific T cellsbasecancer cellcancer therapycancer typechemotherapeutic agentchemotherapychimeric antigen receptorchimeric antigen receptor T cellsclinical applicationclinically relevantcytotoxicitydesigneffector T cellfactor Ahuman modelimage guidedimmunogenicimprovedinnovationirradiationneoplastic cellnon-invasive imagingnon-invasive monitornoveloverexpressionpre-clinicalprostate cancer modelreceptorresponsetheranosticstraffickingtreatment responsetumortumor eradication
中文摘要
项目总结
肿瘤细胞对肿瘤坏死因子α相关的凋亡刺激很敏感
凋亡诱导配体(TRAIL),而正常细胞反应很小。踪迹被证明是
作为单一药物有效,并与某些化疗药物或
放射治疗,导致肿瘤显著消退或完全缓解。越来越多的证据表明
活化T淋巴细胞表面表达的膜结合TRAIL能增强T细胞效应
功能和增强T细胞杀瘤活性。对初级T细胞进行基因工程的能力创造了新的
以及在肿瘤免疫和癌症治疗方面非常有希望的前景。T细胞在体内的转导
编码嵌合抗原受体的基因使T细胞能够识别
免疫原性的或被免疫系统忽略的。此外,基因工程表达的
T细胞的治疗性配体(如TRAIL)可以有效地增强其杀瘤活性。新的战略
肿瘤对基于TRAIL的免疫疗法的敏感性和TRAIL耐药性的调节正在开发中
还有一些可以被翻译到诊所。我们的中心主题和假设是T-TRAIL过度表达
细胞导致肿瘤细胞的凋亡增加,放射和/或化疗对此有积极的影响
T细胞过继免疫治疗中TRAIL介导的肿瘤细胞凋亡及其协同作用
增强T细胞肿瘤靶向性和效应器功能的途径。
在这项应用中,我们建议开发和测试一种新的治疗方法来增强肿瘤细胞的凋亡。
嵌合抗原过表达TRAIL诱导PSMA异质性前列腺癌模型
受体(CAR)-移植的PSMA特异性T细胞。我们将评估膜结合型和分泌型的效果
PSMA特异性T细胞表达的TRAIL形式对其杀伤PSMA阳性和阴性靶的能力的影响。
我们将确定放化疗是否诱导耐TRAIL的肿瘤细胞“敏化”
与增强的T细胞杀瘤功能相关。最终,我们将评估其可行性和敏感性。
用于监测PSMA特异性T细胞活化和TRAIL治疗有效载荷的PET成像
肿瘤。这些过程将使用多报告基因和通过评估T-T的常规成像来监测。
细胞肿瘤的靶向和激活以及肿瘤的反应。
我们的建议补充了MSK和其他癌症中心正在进行的临床研究,探索了新的
旨在增强T细胞效应器功能和改善治疗反应的策略。结果将会是
为前列腺癌患者的临床应用提供临床前支持和理据
其他接受转基因T细胞免疫治疗的癌症。
好了!
英文摘要
PROJECT SUMMARY
Cancer cells have been shown to be sensitive to apoptotic stimulus of tumor necrosis factor α-related
apoptosis-inducing ligand (TRAIL), whereas normal cells showed very little response. TRAIL was shown to be
active as a single agent and exhibited synergistic activity with certain chemotherapeutic agents or
radiotherapy, causing marked regression or complete remission of tumors. There is increasing evidence that
membrane-bound TRAIL expressed on the surface of activated T-lymphocytes can enhance T-cell effector
function and augment T-cell tumoricidal activity. The ability to genetically engineer primary T-cells creates new
and highly promising prospects for tumor immunity and cancer treatment. The transduction of T-cells with
genes encoding chimeric antigen receptors enables T-cell recognition of antigens that are either poorly
immunogenic or ignored by the immune system. In addition, the genetically engineered expression of
therapeutic ligands (e.g. TRAIL) by T-cells can potently increase their tumoricidal activity. New strategies for
tumor sensitization to TRAIL-based immunotherapies and modulation of TRAIL resistance are being developed
and some can be translated to the clinic. Our central theme and hypothesis is that TRAIL overexpression by T-
cells results in augmented apoptosis in tumor cells and that radiation and/or chemotherapy positively affect
TRAIL-mediated tumor apoptosis during T-cell adoptive immunotherapy and can be used as a synergistic
approach to enhance T-cell tumor targeting and effector function.
In this application we propose to develop and test a novel theranostic approach to augment tumor apoptosis in
a prostate cancer model with heterogeneous PSMA levels using TRAIL overexpression by chimeric antigen
receptor (CAR)-grafted PSMA-specific T-cells. We will assess the effect of membrane-bound vs. secretable
forms of TRAIL expressed by PSMA-specific T-cells on their ability to kill PSMA-positive and -negative targets.
We will determine whether radiation/chemotherapy-induced “sensitization” of TRAIL-resistant tumor cells
correlates with an improved T-cell tumoricidal function. Ultimately, we will assess the feasibility and sensitivity
of PET imaging to monitor PSMA-specific T-cell activation and delivery of TRAIL therapeutic payloads to the
tumor. These processes will be monitored using multi-reporter gene and conventional imaging by assessing T-
cell tumor targeting and activation as well as tumor response.
Our proposal complements on-going clinical studies at MSK and other cancer centers by exploring new
strategies designed to enhance T-cell effector function and improve treatment response. The results will
provide preclinical support and justification to move toward clinical application in patients with prostate and
other cancers undergoing immunotherapy with genetically modified T-cells.
!
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
World Molecular Imaging Congress
-
批准号:10753964
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2023
-
负责人:Vladimir Ponomarev
-
依托单位:
Image-guided TRAIL-enhanced CAR T-cell immunotherapy
-
批准号:9892971
-
项目类别:
-
资助金额:$56.78万
-
财政年份:2018
-
负责人:Vladimir Ponomarev
-
依托单位:
Imaging T-cell Activation and Co-stimulation in Prostate Cancer Immunotherapy
-
批准号:8270449
-
项目类别:
-
资助金额:$37.95万
-
财政年份:2011
-
负责人:Vladimir Ponomarev
-
依托单位:
Imaging T-cell Activation and Co-stimulation in Prostate Cancer Immunotherapy
-
批准号:8449954
-
项目类别:
-
资助金额:$35.67万
-
财政年份:2011
-
负责人:Vladimir Ponomarev
-
依托单位:
Imaging T-cell Activation and Co-stimulation in Prostate Cancer Immunotherapy
-
批准号:8163909
-
项目类别:
-
资助金额:$37.29万
-
财政年份:2011
-
负责人:Vladimir Ponomarev
-
依托单位:
Imaging T-cell Activation and Co-stimulation in Prostate Cancer Immunotherapy
-
批准号:8827702
-
项目类别:
-
资助金额:$37.95万
-
财政年份:2011
-
负责人:Vladimir Ponomarev
-
依托单位:
PET Imaging of Genetically Modified Human T-Cells in Prostate Cancer
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批准号:7729462
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项目类别:
-
资助金额:$15.12万
-
财政年份:2008
-
负责人:Vladimir Ponomarev
-
依托单位:
PET Imaging of Tumor Targeting & Role of T Lymphocytes
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批准号:7187345
-
项目类别:
-
资助金额:$34.19万
-
财政年份:2005
-
负责人:Vladimir Ponomarev
-
依托单位:
PET Imaging of Tumor Targeting & Role of T Lymphocytes.
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批准号:7017747
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项目类别:
-
资助金额:$32.28万
-
财政年份:2005
-
负责人:Vladimir Ponomarev
-
依托单位:
PET Imaging of Tumor Targeting & Role of T Lymphocytes
-
批准号:6870056
-
项目类别:
-
资助金额:$33.06万
-
财政年份:2005
-
负责人:Vladimir Ponomarev
-
依托单位:
PET Imaging of Tumor Targeting & Role of T Lymphocytes
-
批准号:7348436
-
项目类别:
-
资助金额:$34.19万
-
财政年份:2005
-
负责人:Vladimir Ponomarev
-
依托单位:
PET Imaging of Genetically Modified Human T-Cells in Prostate Cancer
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批准号:8110592
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项目类别:
-
资助金额:$27.61万
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财政年份:--
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负责人:Vladimir Ponomarev
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依托单位:
PET Imaging of Genetically Modified Human T-Cells in Prostate Cancer
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批准号:7899922
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项目类别:
-
资助金额:$27.61万
-
财政年份:--
-
负责人:Vladimir Ponomarev
-
依托单位:
海外基金