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:
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.
项目摘要
CD19靶向嵌合抗原受体T细胞(CAR-TS)已彻底改变了细胞免疫疗法
难治性B细胞恶性肿瘤,例如B细胞非霍奇金淋巴瘤(B-NHL)和B细胞急性淋巴细胞
白血病(B-All)。尽管完全缓解的速度很高,但接力赛(在第一年内有50%)
仍然是一个关键的挑战,强调了新型CAR-T细胞产品的需求。两种救济模式是
观察到:(i)靶抗原损失和(ii)抗原阳性继电器引起的抗原阴性继电器,这
通过缺乏持久性或损失CAR-TS的功能来介导。商业CD19 CAR-TS雇用
但是,CD28或4-1BB的共刺激结构域已显示出新的OX-40结构域可促进
持久性,细胞毒性和减少疲惫。最后,越来越多的证据表明茎状
CAR-T产品中的记忆T细胞表型与更耐用的响应有关。 Schneider等。 al
开发了具有OX-40共刺激域的Tristepific CD19,CD20,CD22靶向CAR-TS,
与CD19 CAR-TS相比,在临床前淋巴瘤模型中显示出显着的活性。我们验证了这些
内部制造的三角式汽车-TS的发现,并确认其特异性,细胞毒性和
临床前B细胞淋巴瘤模型中的免疫表型适应性。我们的建议旨在解决限制
通过首个人类内部制造的特异性汽车TS的商用CD19 CAR-TS和牛
40个继电器,难治性B细胞malignancys的共刺激域。这些特异性车是
在俄亥俄州立大学的细胞疗法实验室制造
为期6天的制造过程,可以输注类似茎状的记忆汽车-TS。我们假设这一点
Tristecific Cart(i)降低由抗原负克隆逃生介导的继电器的风险; (ii)增强
CAR-TS的持久性将转化为更深,更耐用的临床反应。为了解决这个问题
我们提出了两个目标。在AIM 1中,我们的目标是通过内部制造的第一阶段试用
复发/难治性B-NHL,B-ALL,B-聚二细胞白血病和慢性的患者的Tristexific CAR-TS
淋巴细胞性白血病。主要终点是可行性,Trispific Car-Ts的安全性以及建立
推荐的II期剂量。次要终点是有效的,并且响应持续时间。在AIM 2中,我们的目标是
确定效率的关键机制和对特异性汽车TS的抵抗力。具体来说,我们计划评估:(i)
CAR-TS的持久性及其与完全缓解率,响应持续时间以及其相关性
不良事件的发生率和严重性; (ii)受损的免疫表型和转录特征
CAR-TS和其他单核细胞的功能,使用最高维度的高维光流式细胞仪的状态
并引用后期。
完成该项目后,我们的工作将确定内部制造的可行性
CAR-TS并提供了有关救济和效率机制的见解。
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)

暂无数据
数据更新时间:2024-06-01
Lapo Alinari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:1059453710594537
- 财政年份:2022
- 资助金额:$ 60.93万$ 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:1034291510342915
- 财政年份:2022
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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:1009282110092821
- 财政年份:2018
- 资助金额:$ 60.93万$ 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:95055249505524
- 财政年份:2018
- 资助金额:$ 60.93万$ 60.93万
- 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
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- 批准号:1036045210360452
- 财政年份:2018
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Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:1055334110553341
- 财政年份:1997
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Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
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- 财政年份:1997
- 资助金额:$ 60.93万$ 60.93万
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Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:1009001210090012
- 财政年份:1997
- 资助金额:$ 60.93万$ 60.93万
- 项目类别:
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