BIOPHYSICAL TUNING OF CHIMERIC ANTIGEN RECEPTOR (CAR) SIGNALING FOR SAFE AND EFFECTIVE T CELL IMMUNOTHERAPY
嵌合抗原受体 (CAR) 信号转导的生物物理调节以实现安全有效的 T 细胞免疫治疗
基本信息
- 批准号:10284715
- 负责人:
- 金额:$ 19.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adenocarcinoma CellAdoptionAdoptive Cell TransfersAdverse effectsAffectAntibodiesAntigen ReceptorsAntigen TargetingAntigensAntitumor ResponseAutoimmuneAutoimmune DiseasesAutologousB lymphoid malignancyB-LymphocytesBiochemicalBiological AssayBiophysicsCAR T cell therapyCD19 AntigensCD19 geneCarcinoembryonic AntigenCell LineCell SurvivalCell physiologyCellular immunotherapyCharacteristicsClinicalCoculture TechniquesCytolysisCytoplasmic TailCytotoxic T-LymphocytesDevelopmentDimensionsDisease remissionEndotheliumEngineeringEquilibriumFluorescence MicroscopyGenerationsGoalsHumanImmunityImmunotherapyIn VitroInflammationInflammatoryInvestigationKineticsKnowledgeLifeLiquid substanceMacrophage ActivationMalignant NeoplasmsMediatingModalityModelingMolecularMusPatientsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPlayProductionPropertyProteinsReceptor SignalingRegimenResolutionRodRoleSafetySerious Adverse EventSignal TransductionSolid NeoplasmSystemT cell responseT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTreatment FailureTreatment-related toxicityTumor Antigensantigen bindingbasecancer immunotherapycancer therapycell killingchimeric antigen receptorchimeric antigen receptor T cellsconnectincytokinecytokine release syndromecytotoxicitydesigneffector T cellexperimental studyextracellularimprovedin vitro testingin vivoleukemialeukemia/lymphomaneoplastic cellnovelreceptorreceptor functionresponsesegregationtreatment responsetrigger pointtumor
项目摘要
ABSTRACT
Adoptive cell therapy (ACT) with autologous T cells is a nascent but potentially transformative modality of
cancer immunotherapy. Redirection of the patient’s own T cells to target tumor antigens is achieved by ex vivo
lentiviral transduction and stable expression of tumor-targeting chimeric antigen receptors (CAR). While CAR-
T cells have shown promise in treating some leukemias and lymphomas, their ex vivo expansion, in vivo
survival, functional phenotype, and response to tumor antigens remain unpredictable, sometimes resulting in
treatment failures or serious adverse events – including life-threatening cytokine release syndrome (CRS). Our
overall objective is to apply well-established mechanistic principles of antigen receptor signal transduction to
design CARs with improved safety profiles that more reliably target tumor antigens. Second generation CARs
are comprised of an extracellular antibody-like antigen-binding domain, fused to a diverse range of
hinge/spacer sequences, followed by transmembrane and cytoplasmic signaling domains that are derived from
T cell costimulatory receptors and the T cell antigen receptor (TCR) zeta chain. Although it is well known that
the choice of spacer can critically affect CAR function, no clear mechanistic principles have been identified that
can account for the exquisite sensitivity of CARs to spacer properties. Our preliminary investigations place a
well-understood mechanism of TCR triggering, the kinetic-segregation (K-S) mechanism, at the center of CAR
signaling, and establishes that spacer size is the key characteristic of the ectodomain that determines CAR
triggering. We show, using well-characterized xenogeneic spacers of varying size, that the K-S mechanism can
be exploited to biophysically modulate CAR-T cell signaling. A range of CAR-T cell activation phenotypes can
be produced through size-based tuning, including CAR-T cells that retain high cytolytic activity without
inflammatory cytokine production. In this proposal, we aim to exploit K-S principles to tune the size of CARs
using novel humanized spacers for effective recognition of tumor antigens and high tumor cell killing, but
without excessive inflammatory cytokine production. To achieve this, we will systematically vary the
ectodomain size of humanized CARs using novel syngeneic spacers to identify signaling thresholds that
engage T cell cytolytic function, but not the cytokine release machinery. For these mechanism-oriented
investigations, we will employ in vitro biochemical and co-culture assays of T cell function, along with super-
resolution fluorescence microscopy. We will then proceed to test in vitro-tuned CAR designs for in vivo tumor
killing efficacy and cytokine release profiles using murine liquid and solid tumor models. We anticipate that
these novel CARs, designed using K-S principles, will be useful for improving the safety and efficacy of ACT
regimens.
摘要
使用自体T细胞的免疫细胞疗法(ACT)是一种新生但具有潜在变革性的免疫治疗模式。
癌症免疫疗法患者自身T细胞向靶向肿瘤抗原的重定向通过离体免疫调节来实现。
慢病毒转导和肿瘤靶向嵌合抗原受体(CAR)的稳定表达。虽然汽车-
T细胞在治疗一些白血病和淋巴瘤、它们的离体扩增、体内增殖和免疫应答方面已经显示出前景。
存活、功能表型和对肿瘤抗原反应仍然不可预测,有时导致
治疗失败或严重不良事件-包括危及生命的细胞因子释放综合征(CRS)。我们
总的目标是将抗原受体信号转导的成熟机制原理应用于
设计安全性更高的汽车,更可靠地靶向肿瘤抗原。第二代汽车
由细胞外抗体样抗原结合结构域组成,融合到各种各样的
铰链/间隔区序列,随后是衍生自
T细胞共刺激受体和T细胞抗原受体(TCR)ζ链。尽管众所周知,
间隔区的选择可严重影响CAR功能,但尚未鉴定出明确的机制原理,
可以解释汽车对间隔区性质的灵敏度。我们的初步调查显示
TCR触发的一种众所周知的机制,即CAR中心的动力学分离(K-S)机制,
信号传导,并确定间隔区大小是决定CAR的胞外域的关键特征
触发。我们表明,使用不同大小的良好表征的异种间隔区,K-S机制可以
用于生物药理学调节CAR-T细胞信号传导。一系列CAR-T细胞活化表型可以
通过基于大小的调整产生,包括保留高细胞溶解活性而不
炎性细胞因子产生。在这个建议中,我们的目标是利用K-S原则来调整汽车的大小
使用新的人源化间隔区来有效识别肿瘤抗原和高肿瘤细胞杀伤,
而不产生过多的炎症细胞因子。为了实现这一目标,我们将系统地改变
使用新的同源间隔区来确定人源化汽车的胞外域大小,以鉴定
参与T细胞溶细胞功能,但不参与细胞因子释放机制。对于这些机制导向的
研究中,我们将采用体外生化和共培养试验的T细胞功能,沿着与超级,
分辨率荧光显微镜。然后,我们将继续测试体外调整的CAR设计,用于体内肿瘤
使用鼠液体和实体瘤模型的杀伤效力和细胞因子释放曲线。我们预计
这些新的汽车是根据K-S原理设计的,将有助于提高ACT的安全性和有效性
养生法
项目成果
期刊论文数量(0)
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Kaushik Choudhuri其他文献
Kaushik Choudhuri的其他文献
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{{ truncateString('Kaushik Choudhuri', 18)}}的其他基金
BIOPHYSICAL TUNING OF CHIMERIC ANTIGEN RECEPTOR (CAR) SIGNALING FOR SAFE AND EFFECTIVE T CELL IMMUNOTHERAPY
嵌合抗原受体 (CAR) 信号转导的生物物理调节以实现安全有效的 T 细胞免疫治疗
- 批准号:
10413245 - 财政年份:2021
- 资助金额:
$ 19.5万 - 项目类别:
CELL BIOLOGY AND MOLECULAR MECHANISMS OF HUMAN GAMMA/DELTA T CELL ACTIVATION
人类伽马/德尔塔 T 细胞激活的细胞生物学和分子机制
- 批准号:
10166762 - 财政年份:2019
- 资助金额:
$ 19.5万 - 项目类别:
CELL BIOLOGY AND MOLECULAR MECHANISMS OF HUMAN GAMMA/DELTA T CELL ACTIVATION
人类伽马/德尔塔 T 细胞激活的细胞生物学和分子机制
- 批准号:
10625480 - 财政年份:2019
- 资助金额:
$ 19.5万 - 项目类别:
CELL BIOLOGY AND MOLECULAR MECHANISMS OF HUMAN GAMMA/DELTA T CELL ACTIVATION
人类伽马/德尔塔 T 细胞激活的细胞生物学和分子机制
- 批准号:
10407054 - 财政年份:2019
- 资助金额:
$ 19.5万 - 项目类别:
Cellular and Molecular Basis of Gamma/Delta T Cell Antigen Recognition
Gamma/Delta T 细胞抗原识别的细胞和分子基础
- 批准号:
8663991 - 财政年份:2013
- 资助金额:
$ 19.5万 - 项目类别:
CELLULAR AND MOLECULAR BASIS OF GAMMA/DELTA T CELL ANTIGEN RECOGNITION
Gamma/Delta T 细胞抗原识别的细胞和分子基础
- 批准号:
8300595 - 财政年份:2012
- 资助金额:
$ 19.5万 - 项目类别:
CELLULAR AND MOLECULAR BASIS OF GAMMA/DELTA T CELL ANTIGEN RECOGNITION
Gamma/Delta T 细胞抗原识别的细胞和分子基础
- 批准号:
9039860 - 财政年份:2012
- 资助金额:
$ 19.5万 - 项目类别:
CELLULAR AND MOLECULAR BASIS OF GAMMA/DELTA T CELL ANTIGEN RECOGNITION
Gamma/Delta T 细胞抗原识别的细胞和分子基础
- 批准号:
9101988 - 财政年份:2012
- 资助金额:
$ 19.5万 - 项目类别:
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