Gvl mHA Specific T Cell Responses Prevent AML Relapse Following Allogeneic Stem Cell Transplantation
Gvl mHA 特异性 T 细胞反应可预防同种异体干细胞移植后 AML 复发
基本信息
- 批准号:10436256
- 负责人:
- 金额:$ 52.52万
- 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:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressAllogenicAntigen PresentationAntigen TargetingAutomobile DrivingBehavior TherapyBiochemicalBiological AssayCD8-Positive T-LymphocytesCause of DeathCell-Mediated CytolysisCellsClinicalClinical ProtocolsDataData SetExposure toFailureFrequenciesGene Expression ProfilingGoalsHematopoieticHematopoietic Stem Cell TransplantationHumanImmuneImmune TargetingImmunologicsImmunotherapeutic agentImmunotherapyIn VitroInvestigationLeadLeukemic CellMajor Histocompatibility ComplexMapsMass Spectrum AnalysisMeasurementMeasuresMediatingMethodsMinor Histocompatibility AntigensMutationOutcomePatientsPhenotypePopulationPredispositionPreventionProtocols documentationRecurrent diseaseRelapseResearchResearch ProposalsResistanceRoleSamplingSpecificityStatistical ModelsStem cell transplantT cell responseT-LymphocyteTechnologyTestingTimeTissue BanksTransplant RecipientsTreatment-related toxicityWorkacute myeloid leukemia cellantigen-specific T cellscomputational pipelinescomputerized toolscurative treatmentscytotoxicitydisorder riskdonor stem cellgenetic variantgraft vs host diseasegraft vs leukemia effecthematopoietic tissuehigh riskhuman tissueimmunogenicityimprovedin vivoleukemialeukemia relapseneoantigensnovelpressurepreventresistance mechanismresponsesingle-cell RNA sequencingtranscriptometumor
项目摘要
PROJECT ABSTRACT
Allogeneic stem cell transplantation (SCT) is a curative therapy for high-risk acute myeloid leukemia
(AML); however, relapse remains the leading cause of death post-SCT. AML cures post-SCT depend upon
both the intensity of the conditioning therapy and the ability of donor immune cells to recognize and destroy
host leukemia cells via the graft versus leukemia effect (GvL). AML has a low mutational burden and therefore
a low number of predicted tumor specific neoantigens. Consequently, GvL is most likely mediated by donor T
cell recognition of minor histocompatibility antigens (mHA) presented on leukemia (and/or hematopoietic) cells
by MHC class I and II. This general concept has not been tested in detail however, because of limitations in
predicting, identifying and then validating the mHA responsible for the GVL effect in any given SCT recipient.
To more fully address the role of GvL mHA responses in controlling AML, we will investigate GvL
responses in primary human samples to test our central hypothesis that AML relapse after SCT results from
insufficient donor T cell responses to GvL mHA. To test this hypothesis, we will leverage a human tissue
collection protocol in HLA-matched related donor (MRD) SCTs to measure the global magnitude and diversity
of donor derived GvL mHA specific T cell responses in SCT. To accomplish this goal, we will determine the in
vitro immunogenicity of computationally predicted and biochemically confirmed (by targeted mass
spectrometry) GvL mHA using a combination of ELISpot, single T cell microraft array cytotoxicity, and single T
cell microraft array proliferation measurements. We will map the TCRβ sequences of the GvL mHA specific T
cells onto the TCRβ repertoires of alloreactive T cells post-SCT. We will also investigate the intrinsic resistance
to GvL mHA specific T cell mediated cytotoxicity in AML blasts that relapse following SCT using our microraft
arrays, and we will associate resistance to GvL mHA specific T cell cytotoxicity with differences in
transcriptome profiles measured by single cell RNA sequencing.
The research in this proposal will provide understanding of the role of GvL mHA in control of AML post-
SCT. Because SCT is the most effective form of immunotherapy for AML at this time, our investigations into
the magnitude and diversity of mHA targets required to achieve effective AML control could lead to rational
improvements in the practice of SCT and immunotherapeutic strategies aimed at enhancing GvL mHA
targeting without increasing graft versus host disease risk.
项目摘要
异基因造血干细胞移植是治疗高危急性髓系白血病的有效方法
(AML)然而,复发仍然是SCT后死亡的主要原因。SCT后AML的治愈取决于
调节治疗的强度和供体免疫细胞识别和破坏的能力
通过移植物抗白血病效应(GvL)抑制宿主白血病细胞。AML具有低突变负担,因此
预测的肿瘤特异性新抗原的数量较少。因此,GvL很可能是由供体T介导的
白血病(和/或造血)细胞上呈递的次要组织相容性抗原(mHA)的细胞识别
MHC I类和II类。然而,由于技术上的限制,这个一般概念还没有得到详细的测试。
预测、鉴定然后验证在任何给定SCT接受者中负责GVL效应的mHA。
为了更全面地阐述GvL mHA反应在控制AML中的作用,我们将研究GvL mHA反应在AML中的作用。
在原代人类样本中的反应,以检验我们的中心假设,即SCT后AML复发是由于
供体T细胞对GvL mHA的应答不足。为了验证这一假设,我们将利用人体组织
HLA匹配的相关供体(MRD)SCT的采集方案,以测量全球范围内的数量和多样性
SCT中供体来源的GvL mHA特异性T细胞应答。为了实现这一目标,我们将确定
计算预测和生化证实的体外免疫原性(通过靶向质量
使用ELISpot、单个T细胞微阵列细胞毒性和单个T细胞微阵列细胞毒性的组合,
细胞微阵列增殖测量。我们将绘制GvL mHA特异性T细胞的TCRβ序列,
在SCT后将细胞转移到同种异体反应性T细胞的TCRβ库上。我们还将研究固有电阻
在SCT后复发的AML原始细胞中,使用我们的微阵列检测GvL mHA特异性T细胞介导的细胞毒性。
我们将把对GvL mHA特异性T细胞毒性的抗性与
通过单细胞RNA测序测量转录组谱。
本提案中的研究将提供对GvL mHA在AML后控制中的作用的理解,
SCT。因为SCT是目前AML最有效的免疫治疗形式,我们对
实现有效的反洗钱控制所需的mHA目标的规模和多样性可能导致合理的
SCT实践的改进和旨在增强GvL mHA的免疫策略
靶向而不增加移植物抗宿主病风险。
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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Benjamin G Vincent其他文献
Anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation in patients with high-risk CD30sup+/sup lymphoma: a phase 1 study
抗 CD30 CAR T 细胞作为高危 CD30⁺/⁺淋巴瘤患者自体造血干细胞移植后的巩固治疗:一项 1 期研究
- DOI:
10.1016/s2352-3026(24)00064-4 - 发表时间:
2024-05-01 - 期刊:
- 影响因子:17.700
- 作者:
Natalie S Grover;George Hucks;Marcie L Riches;Anastasia Ivanova;Dominic T Moore;Thomas C Shea;Mary Beth Seegars;Paul M Armistead;Kimberly A Kasow;Anne W Beaven;Christopher Dittus;James M Coghill;Katarzyna J Jamieson;Benjamin G Vincent;William A Wood;Catherine Cheng;Julia Kaitlin Morrison;John West;Tammy Cavallo;Gianpietro Dotti;Barbara Savoldo - 通讯作者:
Barbara Savoldo
Benjamin G Vincent的其他文献
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{{ truncateString('Benjamin G Vincent', 18)}}的其他基金
Gvl mHA Specific T Cell Responses Prevent AML Relapse Following Allogeneic Stem Cell Transplantation
Gvl mHA 特异性 T 细胞反应可预防同种异体干细胞移植后 AML 复发
- 批准号:
10652626 - 财政年份:2020
- 资助金额:
$ 52.52万 - 项目类别:
Gvl mHA Specific T Cell Responses Prevent AML Relapse Following Allogeneic Stem Cell Transplantation
Gvl mHA 特异性 T 细胞反应可预防同种异体干细胞移植后 AML 复发
- 批准号:
10202516 - 财政年份:2020
- 资助金额:
$ 52.52万 - 项目类别:
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