Advancing CAR T cell therapy for solid tumors
推进实体瘤 CAR T 细胞疗法
基本信息
- 批准号:10252515
- 负责人:
- 金额:$ 42.29万
- 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:2021-09-14 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenocarcinoma CellAntigen TargetingAppointmentAuthorshipB lymphoid malignancyB-Cell LeukemiaB-LymphocytesBindingBiological SciencesCAR T cell therapyCD19 geneCRISPR/Cas technologyCell LineCell physiologyCellsChestClinicalClinical SciencesClinical TrialsDataDiagnostic radiologic examinationDoctor of PhilosophyDoseEngineeringEnterobacteria phage P1 Cre recombinaseFoundationsFreedomGenerationsGenesGenetic RecombinationGoalsGrantHematopoieticHumanImmuneImmune responseImmunocompetentImmunologyImmunooncologyImmunosuppressionInjectionsInstitutesKRAS2 geneLabelLaboratoriesLeadLeadershipLentivirusLungLung AdenocarcinomaLung NeoplasmsMajor Histocompatibility ComplexMalignant NeoplasmsMalignant neoplasm of lungMapsModelingMusOutcome StudyPaperPatientsPeptidesPharmaceutical PreparationsPre-Clinical ModelRadiationRadiation Dose UnitRadiation OncologyRadiation therapyRegulatory T-LymphocyteResearchResearch PersonnelResidenciesResolutionScienceSignal TransductionSolidSolid NeoplasmSpecificityT-Cell ProliferationT-LymphocyteTNFRSF5 geneTNFSF5 geneTP53 geneTailTechnologyTestingTherapeuticTimeLineTrainingTranslatingValidationVeinsWorkantigen bindingcell killingchimeric antigen receptorchimeric antigen receptor T cellsclinically relevantcourse developmentcytokineeffector T cellexperienceexperimental studyimprovedinnovationinterestleadership developmentmacrophagemouse modelneoplastic cellnovelnovel therapeutic interventionoverexpressionprofessorprogramsreceptorreceptor bindingrecruitresponsesafety testingsuccesstheoriestissue culturetumortumor microenvironmenttumor-immune system interactions
项目摘要
PROJECT SUMMARY/ABSTRACT
Chimeric Antigen Receptors (CAR) are engineered receptors that direct the killing activity of T cells to targets of
interest and have had dramatic results in the treatment of B cell leukemia. However, the application of this
technology to lung tumor remains challenging in part due to inhibitory tumor microenvironments (TME). An
immunosuppressive TME is seen even at the earliest stages of human lung cancer. These tumors are infiltrated
with immunosuppressive cells including macrophages and T regulatory cells, and have a reduction in effector T
cells. Clinical trials using large doses of solid-tumor directed CAR T cells did not find clear radiographic
responses. While numerous approaches to improve CAR T cell persistence and killing of solid tumors have been
developed, to-date, it remains unclear why clinical responses to second-generation CAR T cells have not
reproduced the dramatic success seen in the treatment of B cell malignancies. Evidently, this challenge requires
mechanistic studies that are only possible in clinically meaningful solid tumor models. This proposal aims to
define the factors what have limited CAR T cell efficacy against solid tumors by building an immunocompetent
tumor model and testing novel therapeutic strategies. We propose to develop the first autochthonous solid tumor
model targeted by CAR T cells. This model will allow us to test CAR T cells on tumors that faithfully recapitulate
the immunosuppressive TME. Prior studies have suggested that radiation can alter the TME. We will use this
model to determine if and how radiotherapy can augment CAR T cell killing of solid tumors. Furthermore, recent
gene editing and delivery advances in CAR T cells have created new avenues to develop novel CAR T cell
therapies that require immunocompetent models for preclinical validation and safety testing. We will use this
platform to test different therapeutic strategies to overcome the immunosuppressive TME that include tumor-
directed radiotherapy, CAR T cell expansion, and gene editing of CAR T cells with CRISPR/Cas9 to avoid
immunosuppressive interactions or reverse them. These experiments will aid in the advancement of CAR T cell
therapy for solid tumors and provide a foundation to determine the applicability of TME-directed approaches to
other targetable solid malignancies.
项目总结/摘要
嵌合抗原受体(CAR)是将T细胞的杀伤活性引导至靶点的工程化受体。
并在治疗B细胞白血病方面取得了显著的效果。然而,这一应用
然而,使用生物技术治疗肺肿瘤仍然具有挑战性,部分原因是抑制性肿瘤微环境(TME)。一个
免疫抑制性TME甚至在人肺癌的最早期就被发现。这些肿瘤已经浸润
与免疫抑制细胞包括巨噬细胞和T调节细胞,并有减少效应T细胞,
细胞使用大剂量实体瘤导向的CAR T细胞的临床试验没有发现明确的放射学
应答虽然已经有许多方法来改善CAR T细胞的持久性和对实体瘤的杀伤,
到目前为止,还不清楚为什么对第二代CAR T细胞的临床反应没有
重现了治疗B细胞恶性肿瘤的巨大成功。显然,这项挑战需要
机制研究仅可能在具有临床意义的实体瘤模型中进行。这项建议旨在
通过构建免疫活性的CAR T细胞,确定限制CAR T细胞对实体瘤疗效的因素。
肿瘤模型和测试新的治疗策略。我们计划在第一个人体内
CAR T细胞靶向的模型。这种模型将使我们能够在肿瘤上测试CAR T细胞,
免疫抑制性TME。先前的研究表明,辐射可以改变TME。我们将使用这个
模型,以确定放射治疗是否以及如何增强实体瘤的CAR T细胞杀伤。此外,最近
CAR T细胞的基因编辑和递送进展为开发新型CAR T细胞创造了新的途径
需要免疫活性模型进行临床前验证和安全性测试的治疗。我们将使用这个
测试不同治疗策略的平台,以克服包括肿瘤在内的免疫抑制性TME
定向放疗,CAR T细胞扩增,以及用CRISPR/Cas9对CAR T细胞进行基因编辑,以避免
免疫抑制相互作用或逆转它们。这些实验将有助于CAR T细胞的发展。
为实体瘤的治疗提供了基础,以确定TME导向方法的适用性,
其他可靶向的实体恶性肿瘤。
项目成果
期刊论文数量(0)
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Jalal Ahmed其他文献
Jalal Ahmed的其他文献
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{{ truncateString('Jalal Ahmed', 18)}}的其他基金
Defining the Hematopoietic Stem Cell Niche in the Fetal Liver
定义胎儿肝脏中的造血干细胞生态位
- 批准号:
8717379 - 财政年份:2014
- 资助金额:
$ 42.29万 - 项目类别:
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