Biomarkers and Therapeutic Targets in Tumor Microenvironment and Metastasis
肿瘤微环境和转移中的生物标志物和治疗靶点
基本信息
- 批准号:10926187
- 负责人:
- 金额:$ 119.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAdjuvant TherapyAdultAgingAreaBiologicalBiological AssayBiological MarkersBloodBlood VesselsBone MarrowCD8-Positive T-LymphocytesCSF1R geneCell CommunicationCell LineCell LineageCell TherapyCell physiologyCellsChemotherapy and/or radiationChildhoodChildhood Solid NeoplasmChronic DiseaseClinicalClinical TrialsCollaborationsColony-Stimulating FactorsCytometryCytotoxic T-LymphocytesDataDevelopmentDiseaseDisseminated Malignant NeoplasmDistantEffectivenessEndothelial CellsEndotheliumEngineeringEnrollmentEpigenetic ProcessEwings sarcomaExcisionExtracellular MatrixFLT3 geneFibrinogenFibroblastsFlow CytometryGene Expression ProfileGeneticGenetic EngineeringGenetic TranscriptionGiant Cell TumorsGrowthGrowth and Development functionHeart DiseasesHematopoieticHematopoietic stem cellsHumanImageImmuneImmune TargetingImmune responseImmune systemImmunofluorescence ImmunologicImmunosuppressionImmunotherapyIndividualInflammatoryInstitutional Review BoardsInvestigationLaboratoriesLongevityLongitudinal StudiesLuciferasesMacrophageMacrophage Colony-Stimulating FactorMalignant NeoplasmsMeasuresMediatingMediatorMesenchymalMetabolicModelingMolecularMonitorMusMyelogenousMyeloid CellsMyeloid-derived suppressor cellsNeoplasm MetastasisNeuroblastomaNormal tissue morphologyOrgan TransplantationPatientsPericytesPhagocytosisPhasePlayPopulationPre-Clinical ModelPrimary NeoplasmProcessRecurrent Malignant NeoplasmRecurrent diseaseRelapseRhabdomyosarcomaRiskRoleShapesSignal TransductionSiteSolid NeoplasmStromal CellsSupporting CellSystemT cell responseT cell therapyT-LymphocyteTestingTherapeuticTissuesTranslatingTranslational ResearchTransplant-Related DisorderTreatment EfficacyTumor Cell LineTumor ImmunityTumor MarkersUniversitiesVascular DiseasesWorkbone circulationcancer recurrencecell behaviorcell typechimeric antigen receptor T cellsconventional therapycytotoxicitydelivery vehicleendothelial stem cellexperimental studyfightinghematopoietic stem cell nichehigh riskimmune phagocytosisimmunoregulationimprovedin vitro Modelin vivoindividualized medicineinhibitorinsightmicrovesiclesmonocytemyeloid cell developmentneoplastic cellnon-geneticnovelosteosarcomapediatric patientspre-clinicalpreclinical studypredictive toolsprogenitorprognostic toolprogramsrare cancerreceptorrecruitrepositoryresponsesingle cell sequencingspecific biomarkersstandard carestem cellstargeted treatmenttherapeutic targettherapy designtherapy developmenttissue regenerationtissue repairtranscriptomicstumortumor microenvironmenttumor progressiontumor xenografttumorigenesisvesicular release
项目摘要
As one of the crucial steps in metastatic progression requires tumor to successfully interact with its local microenvironment, it follows that targeting this cross-talk may be an attractive adjuvant to standard treatment approaches. We are focused on developing therapies that can target and modulate the associated tumor recruited host immune and stromal cells. We have an IRB approved biological repository study to obtain blood, bone marrow, tumor and adjacent normal tissue when available from patients with malignancy and healthy donors. In addition to on-going studies of measuring and characterizing the circulating bone marrow-derived progenitor, immune, endothelial and mesenchymal cells that may be altered in the setting of cancer and other chronic diseases, we have more recently been developing functional assays for human circulating monocytes. Utilizing both quantification and functional assays, including flow cytometry and immune suppression and phagocytosis assays, we are assessing the circulating bone marrow-derived myeloid cell populations in pediatric and adult patients with malignancies. We have broadened our investigations to better understand the changes in the hematopoietic stem cell niche that results in alterations in immune milieu in response to a growing primary tumor. These studies now include in addition to monitoring hematopoietic and endothelial progenitor cells but also CD4 and CD8 T cells and myeloid cells including classical, intermediate and non-classical monocytes, MDSCs and M1 and M2 macrophages and stromal cell populations. Furthermore, we measure circulating microvesicles released by tumor cells and tumor associated myeloid and stromal cells that may impact important cell behavior and are known to be critical to cell-cell communication. We have on-going investigations to explore circulating monocytes and monocyte function and the impact on metastatic risk. Our recent studies have determined host cell plasticity and cell state determine the microvesicles released from these cells and this plasticity in perivascular cells play key roles in regulating metastasis. We are currently investigating markers of this perivascular cell plasticity as a predictor of metastasis and response to conventional therapies and immune based therapies. We have on-going studies and a collaboration with Lynn Hedrick at University of Georgia examining monocyte subpopulations and functions in metastasis and as a biomarker of metastasis. We have established multiple pre-clinical models for testing microenvironment-targeting therapy in pediatric solid tumors. Utilizing a Ewings sarcoma (EWS) xenograft tumor cell line and two syngeneic models- rhabdomyosarcoma (RMS) cell line and an osteosarcoma (OS) cell line we have performed flow cytometry and immunofluorescence to demonstrate the influx of myeloid cells and alterations in stromal cell populations in the tumor and pre-metastatic tissues. We also monitor metastatic progression in a resection model using luciferase imaging. In this fashion, pre-metastatic, metastatic colonization and progression to visible metastasis can be followed and compared in treated and untreated groups without requiring multiple terminal end points. We are conducting pre-clinical investigations utilizing inhibitors targeting stromal cell plasticity specifically to assess impact on metastatic progression. We also now have a marker of tumor associated fibroblast activation and stromal cell lineage tracing mice in order to monitor activation of these cells in this process. We have performed serial in vivo mouse experiments examining modulation of myeloid cells and stromal cells to determine their impact on metastatic progression. We are using different investigational agents to determine their specific impact on each microenvironmental cell. These pre-clinical studies will answer whether this approach to treatment may likely be a good window for targeting the recruitment of these microenvironment tumor-associated cells that support tumor progression. Our studies using a colony stimulating factor -one receptor (csf1-R) inhibitor revealed that these models of RMS and Ewings sarcoma secrete a good deal of CSF-1 and lead to the recruitment of CSF-1R expressing cells. These cells are found in early metastatic sites and are immune suppressive and can protect disseminated tumor cells from cytotoxic T cell activity. We are working on developing approaches to reversing myeloid mediated immunosuppression and promote myeloid mediated anti-tumor T cell responses. We are performing studies to determine the critical effectors of this cytotoxicity. We have also established a good in vitro model to understand the role of tumor-secreted factors on myeloid cell development and stromal cell plasticity and function and investigating different approaches to modulating this process. We have studies examining myeloid cell function and exploring activators and inhibitors of these functions including the myeloid polarization process and phagocytosis. We also have studies exploring the activation and expansion of stromal cell populations that promote metastasis. We completed the Phase I portion of Pexidartinib which inihibits FLT3, Kit and CSF1R. We are now enrolling on the expanded Phase I in pediatric patients with tenosynovial giant cell tumor for open access approval for this agent for pediatric patients as it is approved for this tumor in adults. We are also actively planning a new trial to target immune suppressive myeloid cells. We have developed a new cell therapy based on genetically engineering myeloid cells (GEMys) that can be novel delivery vehicles given their propensity to accumulate in tumor and metastatic sites. These cells can be engineered to deliver Il12 into the tumor milieu and reprogram multiple cell types, change gene transcriptional signatures and reverse immune suppression and enhance anti-tumor immunity. We have developed humanized murine systems to examine human cell therapy with advanced human tumors. On going work to bring this to clinical setting is on-going and harnessing myeloid cells for introduction of signaling in tumor microenvironment. These investigations also include stromal cells and extracellular matrix remodeling. Single cell sequencing can provide exquisite detail of individual cell cluster transcriptional programs. Our laboratory has begun performing single cell sequencing of rare tumors to investigate tumor and microenvironmental interactions. Such studies can be invaluable for tumor and microenvironment genetic and non genetic interactions that provide insights to targeting cross talk and unique aspects of both tumor and associated microenvironment. We have recently leveraged the data we have generated from our first clinical trial of chimeric antigen receptor T cells targeting GD2 in patients with osteosarcoma and neuroblastoma. This collaboration with Dr. Lynn Hedrick and team now at University of Georgia and Dr. Mackall and team at Stanford has allowed deep transcriptomic, mass cytometry and epigenetic investigations into immune response in patients on CART trial. We found that myeloid cells are key regulators of the CART cells. We have that myeloid cells depending on the subpopulations and their receptors can be helpful in promoting effective anti-tumor immunity and conversely myeloid subpopulations can also limit CART expansion. These studies speak to the diversity of myeloid populations and their functions and importance of studying these aspects. These investigations are shaping a new understanding of myeloid mediators of CART expansion and may ultimately impact efficacy and serve as a path to combine myeloid and T cell based therapies. Furthermore, myeloid markers of CAR efficacy will be further explored in other clinical trials to more completely evaluate the markers across solid tumor trials.
由于转移进展的关键步骤之一需要肿瘤与其局部微环境成功相互作用,因此针对这种相互作用可能是标准治疗方法的有吸引力的辅助剂。我们专注于开发能够靶向和调节相关肿瘤招募的宿主免疫细胞和基质细胞的疗法。我们进行了 IRB 批准的生物储存库研究,以获取来自恶性肿瘤患者和健康捐赠者的血液、骨髓、肿瘤和邻近正常组织。除了正在进行的测量和表征循环骨髓来源的祖细胞、免疫细胞、内皮细胞和间充质细胞(这些细胞可能在癌症和其他慢性疾病的情况下发生改变)的研究之外,我们最近还开发了人类循环的功能测定单核细胞。利用定量和功能测定(包括流式细胞术、免疫抑制和吞噬测定),我们正在评估儿科和成人恶性肿瘤患者的循环骨髓源性骨髓细胞群。我们扩大了研究范围,以更好地了解造血干细胞生态位的变化,这些变化导致免疫环境发生变化,以应对不断生长的原发肿瘤。这些研究现在除了监测造血和内皮祖细胞外,还包括 CD4 和 CD8 T 细胞以及骨髓细胞,包括经典、中间和非经典单核细胞、MDSC 以及 M1 和 M2 巨噬细胞和基质细胞群。此外,我们还测量肿瘤细胞以及肿瘤相关骨髓细胞和基质细胞释放的循环微泡,这些微泡可能影响重要的细胞行为,并且已知对细胞间通讯至关重要。我们正在进行研究,以探索循环单核细胞和单核细胞功能及其对转移风险的影响。我们最近的研究确定了宿主细胞的可塑性和细胞状态决定了这些细胞释放的微泡,血管周围细胞的这种可塑性在调节转移中发挥着关键作用。我们目前正在研究这种血管周围细胞可塑性的标志物,作为转移和对传统疗法和免疫疗法的反应的预测因子。我们正在进行研究,并与佐治亚大学的 Lynn Hedrick 合作,检查单核细胞亚群和转移中的功能以及作为转移的生物标志物。我们建立了多个临床前模型来测试儿科实体瘤的微环境靶向治疗。利用尤文氏肉瘤 (EWS) 异种移植肿瘤细胞系和两种同基因模型 - 横纹肌肉瘤 (RMS) 细胞系和骨肉瘤 (OS) 细胞系,我们进行了流式细胞术和免疫荧光分析,以证明骨髓细胞的流入和基质细胞群的变化在肿瘤和转移前组织中。我们还使用荧光素酶成像监测切除模型中的转移进展。以这种方式,可以在治疗组和未治疗组中跟踪和比较转移前、转移性定植以及进展为可见转移,而不需要多个终点。我们正在利用针对基质细胞可塑性的抑制剂进行临床前研究,专门评估对转移进展的影响。我们现在还拥有肿瘤相关成纤维细胞激活和基质细胞谱系追踪小鼠的标记,以便监测这些细胞在此过程中的激活。我们进行了一系列体内小鼠实验,检查骨髓细胞和基质细胞的调节,以确定它们对转移进展的影响。我们正在使用不同的研究药物来确定它们对每个微环境细胞的具体影响。这些临床前研究将回答这种治疗方法是否可能是针对招募这些支持肿瘤进展的微环境肿瘤相关细胞的良好窗口。我们使用集落刺激因子一受体 (csf1-R) 抑制剂进行的研究表明,这些 RMS 和尤文氏肉瘤模型分泌大量 CSF-1,并导致 CSF-1R 表达细胞的募集。这些细胞存在于早期转移部位,具有免疫抑制作用,可以保护播散的肿瘤细胞免受细胞毒性 T 细胞活性的影响。我们正在致力于开发逆转骨髓介导的免疫抑制并促进骨髓介导的抗肿瘤 T 细胞反应的方法。我们正在进行研究以确定这种细胞毒性的关键效应器。我们还建立了一个良好的体外模型,以了解肿瘤分泌因子对骨髓细胞发育和基质细胞可塑性和功能的作用,并研究调节这一过程的不同方法。我们的研究检查了骨髓细胞的功能,并探索了这些功能的激活剂和抑制剂,包括骨髓极化过程和吞噬作用。我们还有研究探索促进转移的基质细胞群的激活和扩张。我们完成了 Pexidartinib 的 I 期部分,该部分抑制 FLT3、Kit 和 CSF1R。我们现在正在招募患有腱滑膜巨细胞瘤的儿科患者的扩展一期临床试验,以开放获取批准该药物用于儿科患者,因为它已被批准用于治疗成人的这种肿瘤。我们还积极计划一项针对免疫抑制性骨髓细胞的新试验。我们开发了一种基于基因工程骨髓细胞 (GEMys) 的新细胞疗法,鉴于其在肿瘤和转移部位积聚的倾向,它可以成为新型输送载体。这些细胞可以被设计为将 Il12 传递到肿瘤环境中并重新编程多种细胞类型、改变基因转录特征、逆转免疫抑制并增强抗肿瘤免疫力。我们开发了人源化小鼠系统来检查晚期人类肿瘤的人类细胞疗法。将其引入临床的工作正在进行中,并利用骨髓细胞在肿瘤微环境中引入信号传导。这些研究还包括基质细胞和细胞外基质重塑。单细胞测序可以提供单个细胞簇转录程序的精致细节。我们的实验室已开始对罕见肿瘤进行单细胞测序,以研究肿瘤和微环境的相互作用。此类研究对于肿瘤和微环境的遗传和非遗传相互作用具有无价的价值,它们为靶向肿瘤和相关微环境的串扰和独特方面提供了见解。我们最近利用了我们在骨肉瘤和神经母细胞瘤患者中针对 GD2 进行嵌合抗原受体 T 细胞的首次临床试验中获得的数据。与佐治亚大学的 Lynn Hedrick 博士和团队以及斯坦福大学的 Mackall 博士和团队合作,可以对 CART 试验患者的免疫反应进行深入的转录组学、质谱流式细胞术和表观遗传学研究。我们发现骨髓细胞是 CART 细胞的关键调节因子。我们发现,取决于亚群及其受体的骨髓细胞有助于促进有效的抗肿瘤免疫,相反,骨髓细胞亚群也可以限制 CART 扩增。这些研究说明了骨髓细胞群的多样性及其功能以及研究这些方面的重要性。这些研究正在形成对 CART 扩增的骨髓介质的新认识,并可能最终影响疗效,并成为结合骨髓和 T 细胞疗法的途径。此外,CAR功效的骨髓标志物将在其他临床试验中进一步探索,以更全面地评估实体瘤试验中的标志物。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma.
生物标志物与滑膜肉瘤患者对 NY-ESO-1 TCR T 细胞的反应相关。
- DOI:
- 发表时间:2022-09-08
- 期刊:
- 影响因子:16.6
- 作者:Gyurdieva, Alexandra;Zajic, Stefan;Chang, Ya;Houseman, E Andres;Zhong, Shan;Kim, Jaegil;Nathenson, Michael;Faitg, Thomas;Woessner, Mary;Turner, David C;Hasan, Aisha N;Glod, John;Kaplan, Rosandra N;D'Angelo, Sandra P;Araujo, Dejka M;Cho
- 通讯作者:Cho
ENABLE (Exportable Notation and Bookmark List Engine): an Interface to Manage Tumor Measurement Data from PACS to Cancer Databases.
ENABLE(可导出符号和书签列表引擎):用于管理从 PACS 到癌症数据库的肿瘤测量数据的接口。
- DOI:
- 发表时间:2017-06
- 期刊:
- 影响因子:4.4
- 作者:Goyal, Nikhil;Apolo, Andrea B;Berman, Eliana D;Bagheri, Mohammad Hadi;Levine, Jason E;Glod, John W;Kaplan, Rosandra N;Machado, Laura B;Folio, Les R
- 通讯作者:Folio, Les R
New fusion sarcomas: histopathology and clinical significance of selected entities.
新的融合肉瘤:所选实体的组织病理学和临床意义。
- DOI:
- 发表时间:2019
- 期刊:
- 影响因子:3.3
- 作者:Miettinen, Markku;Felisiak;Luiña Contreras, Alejandro;Glod, John;Kaplan, Rosandra N;Killian, Jonathan Keith;Lasota, Jerzy
- 通讯作者:Lasota, Jerzy
Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.
破坏 CXCR2 介导的 MDSC 肿瘤运输可增强抗 PD1 功效。
- DOI:
- 发表时间:2014-05-21
- 期刊:
- 影响因子:17.1
- 作者:Highfill, Steven L;Cui, Yongzhi;Giles, Amber J;Smith, Jillian P;Zhang, Hua;Morse, Elizabeth;Kaplan, Rosandra N;Mackall, Crystal L
- 通讯作者:Mackall, Crystal L
MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research.
患有复发性和难治性癌症的儿童和青少年的精准治疗的多维临床组学:癌症研究中心的报告。
- DOI:
- 发表时间:2016-08-01
- 期刊:
- 影响因子:0
- 作者:Chang W;Brohl AS;Patidar R;Sindiri S;Shern JF;Wei JS;Song YK;Yohe ME;Gryder B;Zhang S;Calzone KA;Shivaprasad N;Wen X;Badgett TC;Miettinen M;Hartman KR;League-Pascual JC;Trahair TN;Widemann BC;Merchant MS;Kaplan RN;Lin JC;Khan J
- 通讯作者:Khan J
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Rosandra Kaplan其他文献
Rosandra Kaplan的其他文献
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{{ truncateString('Rosandra Kaplan', 18)}}的其他基金
Biomarkers and Therapeutic Targets in Tumor Microenvironment and Metastasis
肿瘤微环境和转移中的生物标志物和治疗靶点
- 批准号:
10486817 - 财政年份:
- 资助金额:
$ 119.07万 - 项目类别:
Biomarkers and Therapeutic Targets in Tumor Microenvironment and Metastasis
肿瘤微环境和转移中的生物标志物和治疗靶点
- 批准号:
10702532 - 财政年份:
- 资助金额:
$ 119.07万 - 项目类别:
Biomarkers and Therapeutic Targets in Angiogenesis and Metastasis
血管生成和转移中的生物标志物和治疗靶点
- 批准号:
8349478 - 财政年份:
- 资助金额:
$ 119.07万 - 项目类别:
Biomarkers and Therapeutic Targets in Angiogenesis and Metastasis
血管生成和转移中的生物标志物和治疗靶点
- 批准号:
8938065 - 财政年份:
- 资助金额:
$ 119.07万 - 项目类别:
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- 资助金额:
$ 119.07万 - 项目类别:
Design of a Novel Nanocarrier Technology to Drug-Load CAR T cells
用于载药 CAR T 细胞的新型纳米载体技术的设计
- 批准号:
10734365 - 财政年份:2023
- 资助金额:
$ 119.07万 - 项目类别:
Stem cell-derived exosomes to ameliorate chemobrain
干细胞衍生的外泌体改善化学脑
- 批准号:
10584374 - 财政年份:2023
- 资助金额:
$ 119.07万 - 项目类别: