Dual targeting of tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway
通过阻断 IL-33/ST2 通路双重靶向肿瘤微环境和肿瘤细胞
基本信息
- 批准号:10228863
- 负责人:
- 金额:$ 15.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-06 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAdultAllogenicAnnual ReportsAntibodiesBiologicalBiologyBispecific AntibodiesBone MarrowBrain NeoplasmsCAR T cell therapyCD8-Positive T-LymphocytesCell ProliferationCellsChildhood Solid NeoplasmDataDefectDevelopmentFOXP3 geneGoalsHumanIgG1ImmuneImmunityImmunocompetentImmunotherapyInterferon Type IIInterferonsInterleukin-2InterleukinsKnock-outKnowledgeLeadLeukemic CellLiquid substanceLymphocyteMLL-AF9Malignant - descriptorMalignant Childhood NeoplasmMalignant NeoplasmsMembraneMemorial Sloan-Kettering Cancer CenterModelingMolecularMusNCI Center for Cancer ResearchNatureNeuroblastomaNon-MalignantPathway interactionsPatientsPediatric NeoplasmPopulationProcessProteomeRegimenRegulatory T-LymphocyteResearchRoleSignal TransductionSoft tissue sarcomaSolidSolid NeoplasmT-LymphocyteTestingTherapeuticTissue BanksTumor ImmunityTumor-infiltrating immune cellsWild Type MouseWorkXenograft ModelXenograft procedureacute myeloid leukemia cellbasechemotherapycytotoxicexhaustionexperimental studyhematopoietic cell transplantationhigh throughput screeninghumanized mousein vivo Modelinnovationinsightirradiationleukemialeukemia/lymphomamouse modelneoplastic cellneutralizing antibodynovelosteosarcomaoverexpressionpersonalized medicinepublic health relevancereceptorresponserestorationsarcomastandard caretranscriptometreatment planningtumortumor growthtumor microenvironmenttumor-immune system interactionsunpublished worksvirtual
项目摘要
PROJECT SUMMARY/ABSTRACT: A fundamental gap exists in our knowledge of the immunologic tumoral
microenvironment during the development of acute myeloid leukemia (AML) and other deadly childhood
cancers. Bridging of this gap could lead to novel immunotherapies. Our long-term goals are to develop novel
immunotherapies for leukemia and pediatric solid tumors. Our objective in this application is to investigate the
role of Foxp3+ regulatory T cells (Tregs) expressing Stimulation-2 (ST2), the IL-33 receptor in the
microenvironment as well as ST2 on tumoral cells. Our central hypothesis is that we can target the tumoral
microenvironment and tumoral cells by blocking the IL-33/ST2 pathway with neutralizing and bispecific
antibodies that we will develop. This hypothesis was formed based on our unpublished preliminary data
showing that: First, nonmalignant mice deficient in T-bet have elevated numbers of BM-infiltrating ST2+ Tregs
compared to wild-type (WT) mice (45% vs 25%, respectively), suggesting reciprocal roles of ST2/IL33 and T-
bet/interferon-γ (IFN-γ) in Tregs from the BM niche. Second, we observed 10-fold more Tregs expressing
significantly more activation markers in the BM niche of AML-bearing mice than in the nonmalignant niche.
Third, MLL-AF9 AML cell proliferation was significantly lower in mice receiving donor syngeneic ST2 knock-out
(ST2-/-) T cells than in mice receiving donor syngeneic WT T cells (2% vs 17%, respectively). ST2 blockade
also decreased Treg activation (i.e., KLRG1) and increased type 1 signaling in CD8+ T cells as well as
decreased their exhaustion, suggesting restoration of an antitumoral response in ST2-/- mice. The rationale for
this study is that once we are able to understand the biology of the immunological microenvironment in the
malignant niche, we can propose personalized treatment plans to block the tolerogenic pathways. Similarly,
understanding the biology responsible for the overexpression of ST2/IL-33 on the tumoral cell, will help target
this pathway. This hypothesis will be tested with three specific aims: 1) Explore ST2 and IL-33 expression on
tumoral cells and in the tumoral microenvironment from liquid and solid childhood cancers in human and mice;
2) Examine whether ST2/IL-33 blockade can impact tumor immunity in the malignant BM niche and solid tumor
microenvironment as a proof-of-principle of a novel antitumoral immunotherapy; and 3) Optimizing anti-ST2
neutralizing antibodies against murine and human targets for translational purpose. This approach is innovative
because, to our knowledge, the function of ST2+ Tregs in the malignant microenvironment, remains virtually
unexplored. It will also provide biological insights into the nature of ST2+ Tregs and ST2+ tumoral cells in the
microenvironment and determine whether their blockade can restore antitumoral activity and decrease tumoral
proliferation via a dual mechanism. The proposed research is significant because novel antitumoral
immunotherapies that are more targeted and less toxic than classical chemotherapy/irradiation regimens are
needed.
项目摘要/摘要:我们对免疫学肿瘤的认识存在着根本的差距
急性髓系白血病(AML)和其他致命儿童发病过程中的微环境
癌症。弥合这一差距可能会带来新的免疫疗法。我们的长期目标是开发新的
白血病和儿童实体肿瘤的免疫疗法。我们在此应用程序中的目标是调查
表达IL-33受体刺激-2(ST2)的Foxp3+调节性T细胞(Tregs)在慢性粒细胞白血病中的作用
微环境以及ST2对肿瘤细胞的影响。我们的中心假设是我们可以针对肿瘤
中和双特异性阻断IL-33/ST2通路的微环境与肿瘤细胞
我们将产生的抗体。这一假设是基于我们未发表的初步数据而形成的。
结果表明:首先,T-bet基因缺陷的非恶性小鼠骨髓浸润性ST2+Tregs数量增加
与野生型(WT)小鼠(分别为45%和25%)相比,表明ST2/IL33和T-
BET/干扰素-γ(干扰素-γ)在来自BM利基的Treg中。其次,我们观察到10倍以上的Tregs表达
携带AML的小鼠骨髓中的激活标记物显著多于非恶性的小鼠。
第三,在接受供者同基因ST2基因敲除的小鼠中,MLL-AF9 AML细胞的增殖显著降低
(ST2-/-)T细胞多于接受供者同基因WT T细胞的小鼠(分别为2%和17%)。ST2封锁
也降低了Treg的激活(即KLRG1),增加了CD8+T细胞中的1型信号以及
减少了它们的消耗,表明ST2-/-小鼠的抗肿瘤反应恢复了。其基本原理是
这项研究是,一旦我们能够了解免疫微环境的生物学在
恶性的小生境,我们可以提出个体化的治疗方案,阻断耐受的通路。同样,
了解ST2/IL-33在肿瘤细胞上过度表达的生物学机制将有助于靶向
这条路。这一假设将以三个特定的目的进行检验:1)探索ST2和IL-33在
人类和小鼠的液体和固体儿童癌症的肿瘤细胞和肿瘤微环境;
2)检测ST2/IL-33阻断对恶性骨肉瘤瘤巢和实体瘤免疫功能的影响
微环境作为一种新的抗肿瘤免疫疗法的原理验证;以及3)优化抗ST2
针对小鼠和人类靶标的翻译中和抗体。这种方法是创新的。
因为,据我们所知,ST2+Tregs在恶性微环境中的功能几乎仍然存在
未被开发的。它还将提供对ST2+Tregs和ST2+肿瘤细胞本质的生物学见解。
并确定其阻断是否能恢复抗肿瘤活性和减少肿瘤
通过双重机制进行扩散。这项拟议的研究具有重要意义,因为新型抗肿瘤药物
比经典的化疗/放射疗法更有针对性和毒性更低的免疫疗法是
需要的。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor.
- DOI:10.3389/fimmu.2021.761448
- 发表时间:2021
- 期刊:
- 影响因子:7.3
- 作者:Jiang H;Fu D;Bidgoli A;Paczesny S
- 通讯作者:Paczesny S
T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia.
- DOI:10.1136/jitc-2021-002509
- 发表时间:2021-05
- 期刊:
- 影响因子:10.9
- 作者:Hoseini SS;Vadlamudi M;Espinosa-Cotton M;Tran H;Feng Y;Guo HF;Xu H;Cheung I;Cheung NV
- 通讯作者:Cheung NV
Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia.
FLT3 ITD、TET2 和 DNMT3A 的组合杂合性导致侵袭性白血病。
- DOI:10.1172/jci.insight.162016
- 发表时间:2022-09-08
- 期刊:
- 影响因子:8
- 作者:Ramdas, Baskar;Reddy, Palam Lakshmi;Mali, Raghuveer Singh;Pasupuleti, Santhosh Kumar;Zhang, Ji;Kelley, Mark R.;Paczesny, Sophie;Zhang, Chi;Kapur, Reuben
- 通讯作者:Kapur, Reuben
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NAI-KONG V CHEUNG其他文献
NAI-KONG V CHEUNG的其他文献
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{{ truncateString('NAI-KONG V CHEUNG', 18)}}的其他基金
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人源化 3F8 单克隆抗体 (Hu3F8) 在高危人群中的 I 期研究
- 批准号:
8270451 - 财政年份:2011
- 资助金额:
$ 15.31万 - 项目类别:
Phase I Study of Humanized 3F8 Monoclonal Antibody (Hu3F8) in Patients with High-
人源化 3F8 单克隆抗体 (Hu3F8) 在高危人群中的 I 期研究
- 批准号:
8189124 - 财政年份:2011
- 资助金额:
$ 15.31万 - 项目类别:
A novel set of molecular markers to measure metastatic neuroblastoma
一套用于测量转移性神经母细胞瘤的新型分子标记物
- 批准号:
7023377 - 财政年份:2006
- 资助金额:
$ 15.31万 - 项目类别:
A novel set of molecular markers to measure metastatic neuroblastoma
一套用于测量转移性神经母细胞瘤的新型分子标记物
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基于抗体的癌症免疫的植物调节
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- 资助金额:
$ 15.31万 - 项目类别:
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