Trispecific CAR-T cells targeting CD19, CD20 and CD22 to treat B-cell malignancies
靶向 CD19、CD20 和 CD22 的三特异性 CAR-T 细胞治疗 B 细胞恶性肿瘤
基本信息
- 批准号:10735096
- 负责人:
- 金额:$ 60.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-21 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdverse eventAntigen TargetingAntigensB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaB-Cell LymphomasB-Cell NeoplasmB-Cell NonHodgkins LymphomaB-Cell Prolymphocytic LeukemiaBlood Component RemovalBlood specimenCD19 geneCD22 geneCD28 geneCell TherapyCellsCellular Indexing of Transcriptomes and Epitopes by SequencingCellular immunotherapyChronic Lymphocytic LeukemiaClinicalClinical TrialsDevicesDiseaseDisease remissionDoseDown-RegulationEconomically Deprived PopulationEnrollmentEvaluationFDA approvedFlow CytometryFundingGenetic TranscriptionGoalsGood Manufacturing ProcessHarvestImmuneImmunophenotypingImpairmentIn VitroIncidenceInfusion proceduresLaboratoriesLeadLogisticsLymphoblastic LeukemiaLymphomaMS4A1 geneMalignant lymphoid neoplasmMediatingMemoryMethodologyMethodsModelingMononuclearOX40OhioPatientsPatternPhasePhenotypePre-Clinical ModelProliferatingProteinsRecommendationRefractoryRelapseResistanceRisk ReductionSafetySeveritiesSpecificityT memory cellT-LymphocyteTestingTimeTranslatingUniversitiesVeinsWait TimeWorkchimeric antigen receptor T cellscohortcost effectivecytokinecytotoxicitydensityeffective therapyexhaustionfirst-in-humanfitnesshigh dimensionalityhuman studyimprovedin vivoinnovationinsightloss of functionmanufacturemanufacturing processneoplastic cellnext generationnovelnovel strategiesnovel therapeutic interventionparticipant enrollmentpatient subsetsperipheral bloodphase 1 studyphase 2 studyphase I trialpoint of carepre-clinicalpressurepreventprimary endpointrecoverin proteinrelapse riskresponsesafety and feasibilitysecondary endpointstemsuccess
项目摘要
Project summary
CD19 targeted chimeric antigen receptor T cells (CAR-Ts) have revolutionized cellular immunotherapy in
refractory B-cell malignancies such as B-cell Non-Hodgkin’s lymphoma (B-NHL) and B-cell acute lymphoblastic
leukemia (B-ALL). Despite high rates of complete remissions, relapses, 50% of which within the first year,
remain a critical challenge highlighting the need for novel CAR-T cell products. Two patterns of relapse are
observed: (i) Antigen-negative relapses, caused by target antigen loss and (ii) antigen-positive relapses, which
are mediated by lack of persistence or loss of function of the CAR-Ts. Commercial CD19 CAR-Ts employ
either a CD28 or a 4-1BB costimulatory domain however, a novel OX-40 domain has been shown to promote
persistence, cytotoxicity and decrease exhaustion. Finally, increasing evidence suggests that stem-like
memory T cell phenotype in the CAR-T product is associated with more durable responses. Schneider et. al
developed a Trispecific CD19, CD20, CD22-targeting CAR-Ts with an OX-40 costimulatory domain and
showed significant activity in preclinical lymphoma models compared to CD19 CAR-Ts. We validated these
findings with in-house manufactured Trispecific CAR-Ts and confirmed their specificity, cytotoxicity, and
immunophenotypic fitness in preclinical B-cell lymphoma models. Our proposal seeks to address the limitations
of commercial CD19 CAR-Ts through a first-in-human in-house manufactured Trispecific CAR-Ts with an OX-
40 costimulatory domain for relapsed, refractory B-cell malignancies. These trispecific CAR-Ts are
manufactured in the Ohio State University Cell therapy laboratory using the CliniMACS Prodigy device over a
6-day manufacturing process which allows for infusion of stem-like memory CAR-Ts. We hypothesize that
trispecific CARTs will (i) reduce the risk of relapse mediated by antigen negative clonal escape; (ii) enhance
persistence of CAR-Ts which will translate into deeper and more durable clinical responses. To address this,
we propose two Aims. In Aim 1, we aim to conduct a first-in-human phase I trial with in-house manufactured
trispecific CAR-Ts in patients with relapsed/refractory B-NHL, B-ALL, B-prolymphocytic leukemia, and chronic
lymphocytic leukemia. Primary endpoints are feasibility, safety of trispecific CAR-Ts along with establishing a
recommended phase II dose. Secondary endpoints are efficacy and duration of response. In Aim 2, we aim to
identify key mechanisms of efficacy and resistance to trispecific CAR-Ts. Specifically, we plan to assess: (i)
persistence of CAR-Ts and its correlation with complete remission rates, duration of response as well as
incidence and severity of adverse events; (ii) immunophenotypic and transcriptional features of impaired
function of CAR-Ts and other mononuclear cells using state of the art high-dimensional spectral flow cytometry
and CITE-sequencing.
At completion of this project, our work will have established feasibility of in-house manufacturing of trispecific
CAR-Ts and provided insights into mechanisms of relapse and efficacy.
项目总结
CD19靶向嵌合抗原受体T细胞(CAR-ts)使细胞免疫治疗发生了革命性的变化
难治性B细胞恶性肿瘤,如B细胞非霍奇金淋巴瘤(B-NHL)和B细胞急性淋巴母细胞瘤
白血病(B-ALL)。尽管完全缓解率很高,复发,其中50%是在第一年内,
仍然是一个关键挑战,突显了对新型CAR-T细胞产品的需求。复发的两种模式是
观察到:(1)抗原阴性复发,由靶抗原丢失引起;(2)抗原阳性复发,
是由于汽车缺乏持久性或功能丧失所致。商业CD19汽车公司员工
然而,无论是CD28还是4-1BB共刺激结构域,一个新的OX-40结构域都被证明可以促进
持久性、细胞毒性和减少疲劳。最后,越来越多的证据表明,茎状结构
CAR-T产物中的记忆T细胞表型与更持久的反应有关。施耐德等人。阿尔
开发了具有OX-40共刺激结构域的三特异性CD19、CD20、CD22靶向小体,并
与CD19相比,在临床前淋巴瘤模型中显示出显著的活性。我们验证了这些
用内部制造的三特异性CAR的研究结果,证实了它们的特异性、细胞毒性和
临床前B细胞淋巴瘤模型的免疫表型适合性。我们的建议旨在解决这些限制
商业CD19汽车通过第一辆人类内部制造的带有牛的三种特定汽车-
40共刺激区域,用于复发、难治性B细胞恶性肿瘤。这些三合一的汽车是
俄亥俄州立大学细胞治疗实验室使用CliniMACS Prodigy设备
6天的制造工艺,允许输注茎状记忆汽车。我们假设
三特异性CART将(I)降低由抗原阴性克隆性逃逸介导的复发风险;(Ii)增强
CART的持久性,这将转化为更深入和更持久的临床反应。为了解决这个问题,
我们提出了两个目标。在目标1中,我们的目标是用内部制造的产品进行第一阶段的人体试验
复发性/难治性B-NHL、B-ALL、B-早幼粒细胞白血病和慢性白血病患者的三特异性基因片段
淋巴细胞性白血病。主要终点是三种特定汽车的可行性、安全性以及建立一个
推荐的第二阶段剂量。次要终点是疗效和反应持续时间。在目标2中,我们的目标是
确定对三特异性CART的疗效和抗药性的关键机制。具体来说,我们计划评估:(I)
CAR-TS的持续性及其与完全缓解率、反应持续时间的相关性
不良事件的发生率和严重程度;(2)受损的免疫表型和转录特征
用最先进的高维光谱流式细胞术检测CAR-T和其他单个核细胞的功能
并进行引证排序。
在这个项目完成后,我们的工作将建立在内部生产三种规格的可行性
Car-ts,并对复发和疗效机制提供了见解。
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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Lapo Alinari其他文献
Lapo Alinari的其他文献
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{{ truncateString('Lapo Alinari', 18)}}的其他基金
Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma
靶向 c-Myc 过表达大 B 细胞淋巴瘤中的 c-Myc 稳定性
- 批准号:
10594537 - 财政年份:2022
- 资助金额:
$ 60.93万 - 项目类别:
Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma
靶向 c-Myc 过表达大 B 细胞淋巴瘤中的 c-Myc 稳定性
- 批准号:
10342915 - 财政年份:2022
- 资助金额:
$ 60.93万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
10092821 - 财政年份:2018
- 资助金额:
$ 60.93万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
9505524 - 财政年份:2018
- 资助金额:
$ 60.93万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
10360452 - 财政年份:2018
- 资助金额:
$ 60.93万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10553341 - 财政年份:1997
- 资助金额:
$ 60.93万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10333297 - 财政年份:1997
- 资助金额:
$ 60.93万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10090012 - 财政年份:1997
- 资助金额:
$ 60.93万 - 项目类别:
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