Examining the impact of endogenous CD28 signaling on CAR T cells
检查内源性 CD28 信号传导对 CAR T 细胞的影响
基本信息
- 批准号:10318192
- 负责人:
- 金额:$ 8.41万
- 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:2020-12-11 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adoptive ImmunotherapyAffectAntibody ActivationAntigen-Presenting CellsAntigensApplications GrantsAutoimmune DiseasesB lymphoid malignancyB-LymphocytesBiological Response Modifier TherapyCAR T cell therapyCD19 geneCD28 geneCD80 geneCD86 geneCTLA4 geneCancer PatientCell DeathCell LineageCell MaturationCell physiologyCellsClinicalClinical ResearchDataDistalEpigenetic ProcessFDA approvedFunctional disorderGene ExpressionGenesGeneticGoalsHematopoietic NeoplasmsImmuneIn complete remissionKnowledgeLigandsLiteratureMalignant - descriptorMembraneModelingModificationMultiple MyelomaOccupationsPatientsPersonsPharmaceutical PreparationsPharmacologyPhysiologicalPropertyProteinsPublishingReceptor SignalingRefractoryRelapseReportingResearchResistanceRheumatoid ArthritisSignal TransductionSurfaceSurface AntigensT cell responseT-Cell ReceptorT-LymphocyteTestingTreatment FailureUp-Regulationblood treatmentcancer cellcancer typecell killingcellular engineeringcellular transductionchemotherapychimeric antigen receptorchimeric antigen receptor T cellsclinical developmentclinical translationearly phase clinical trialeffector T cellexhaustexhaustionimprovedin vivoinhibitormanufacturing processmutantneoplastic cellnovel strategiesobjective response ratephase II trialpreclinical studyprogramsreceptorrelapse patientsresponsestandard of caretumor
项目摘要
Project Abstract/Summary.
Recent advances in immune cell engineering have revolutionized the treatment of blood cancers. Genetic
modification of T cells, whose physiological job is to kill infected and mutant cells throughout our bodies, with
Chimeric Antigen Receptors (CARs) can redirect T cell killing activity against malignant cells that express certain
target proteins on their surface. CARs are built to mimic physiological T cell signaling, which is unique in its
requirement for two signals provided by the T cell receptor (TCR) and co-receptors, such as CD28, to induce T
cell function. Recent clinical studies in multiple myeloma (MM), a common incurable blood cancer, have shown
that CAR T cells are remarkably effective at treating patients who do not respond to standard of care
chemotherapies. Despite this, most MM patients relapsed within a year of CAR T cell therapy and the cause of
their relapses was not readily apparent. The long-term goal of the project proposed in this grant application is to
use our knowledge or T cell signaling to make CAR T cell therapy for MM more effective. To this end, we have
found that endogenous CD28 on CAR T cells disrupts their ability to kill MM cells that express CD28 stimulatory
proteins CD80 and CD86. However, the same endogenous CD28 is essential for making CAR T cells and we
have also found that the CD28 signal provided during the CAR T cell manufacturing process helps determine
how good of tumor killers CAR T cells become. Proposed studies seek to 1) identify ways to manipulate CD28
signaling during CAR T cell manufacture that can improve their long-term ability to kill MM cells in patients, and
2) determine how endogenous CD28 signaling causes dysfunction of CAR T cells. Results of these studies will
have direct clinical implications because adjustments to the CAR T cell manufacturing process could be rapidly
implemented and a drug that blocks CD28 activation, abatacept, is already used to treat people suffering from
rheumatoid arthritis.
项目摘要/摘要。
免疫细胞工程的最新进展彻底改变了血癌的治疗。遗传
T 细胞的修饰,其生理作用是杀死我们体内受感染和突变的细胞,
嵌合抗原受体 (CAR) 可以重定向 T 细胞杀伤活性,以对抗表达某些表达的恶性细胞。
靶向其表面的蛋白质。 CAR 是为了模仿生理性 T 细胞信号传导而构建的,其独特之处在于
需要 T 细胞受体 (TCR) 和辅助受体(例如 CD28)提供的两种信号来诱导 T
细胞功能。最近针对多发性骨髓瘤 (MM)(一种常见的无法治愈的血癌)的临床研究表明
CAR T 细胞对于治疗对标准护理无反应的患者非常有效
化疗。尽管如此,大多数 MM 患者在接受 CAR T 细胞治疗后一年内复发,其原因是
他们的旧病复发并不明显。本次拨款申请中提出的项目的长期目标是
利用我们的知识或 T 细胞信号传导使 CAR T 细胞疗法对 MM 更加有效。为此,我们有
发现 CAR T 细胞上的内源性 CD28 破坏了它们杀死表达 CD28 刺激性的 MM 细胞的能力
蛋白质 CD80 和 CD86。然而,相同的内源性 CD28 对于制造 CAR T 细胞至关重要,我们
我们还发现,在 CAR T 细胞制造过程中提供的 CD28 信号有助于确定
CAR T 细胞的肿瘤杀手有多强大。拟议的研究旨在 1) 确定操纵 CD28 的方法
CAR T 细胞制造过程中的信号传导可以提高其杀死患者体内 MM 细胞的长期能力,以及
2) 确定内源性CD28信号传导如何导致CAR T细胞功能障碍。这些研究的结果将
具有直接的临床意义,因为对 CAR T 细胞制造工艺的调整可能会迅速发生
一种阻断 CD28 激活的药物阿巴西普 (abatacept) 已被用于治疗患有以下疾病的患者:
类风湿关节炎。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.
- DOI:10.3389/fimmu.2023.1121565
- 发表时间:2023
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
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Scott Henry Olejniczak其他文献
Scott Henry Olejniczak的其他文献
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{{ truncateString('Scott Henry Olejniczak', 18)}}的其他基金
Understanding mechanisms and consequences of T cell co-receptor regulated RNA maturation
了解 T 细胞辅助受体调节 RNA 成熟的机制和后果
- 批准号:
10096361 - 财政年份:2021
- 资助金额:
$ 8.41万 - 项目类别:
Understanding mechanisms and consequences of T cell co-receptor regulated RNA maturation
了解 T 细胞辅助受体调节 RNA 成熟的机制和后果
- 批准号:
10589052 - 财政年份:2021
- 资助金额:
$ 8.41万 - 项目类别:
Understanding mechanisms and consequences of T cell co-receptor regulated RNA maturation
了解 T 细胞辅助受体调节 RNA 成熟的机制和后果
- 批准号:
10383646 - 财政年份:2021
- 资助金额:
$ 8.41万 - 项目类别:
Examining the impact of endogenous CD28 signaling on CAR T cells
检查内源性 CD28 信号传导对 CAR T 细胞的影响
- 批准号:
10113296 - 财政年份:2020
- 资助金额:
$ 8.41万 - 项目类别:
Reciprocal regulation of microRNAs and cancer-associated signaling pathways
microRNA 和癌症相关信号通路的相互调节
- 批准号:
9060904 - 财政年份:2015
- 资助金额:
$ 8.41万 - 项目类别:
Reciprocal regulation of microRNAs and cancer-associated signaling pathways
microRNA 和癌症相关信号通路的相互调节
- 批准号:
9015979 - 财政年份:2015
- 资助金额:
$ 8.41万 - 项目类别:
Reciprocal regulation of microRNAs and cancer-associated signaling pathways
microRNA 和癌症相关信号通路的相互调节
- 批准号:
8634982 - 财政年份:2014
- 资助金额:
$ 8.41万 - 项目类别:
Reciprocal regulation of microRNAs and cancer-associated signaling pathways
microRNA 和癌症相关信号通路的相互调节
- 批准号:
8790432 - 财政年份:2014
- 资助金额:
$ 8.41万 - 项目类别:
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