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

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:
    10594537
    10594537
  • 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:
    10342915
    10342915
  • 财政年份:
    2022
  • 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:
    10092821
    10092821
  • 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:
    9505524
    9505524
  • 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:
    10360452
    10360452
  • 财政年份:
    2018
  • 资助金额:
    $ 60.93万
    $ 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
    10553341
  • 财政年份:
    1997
  • 资助金额:
    $ 60.93万
    $ 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
    10333297
  • 财政年份:
    1997
  • 资助金额:
    $ 60.93万
    $ 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
    10090012
  • 财政年份:
    1997
  • 资助金额:
    $ 60.93万
    $ 60.93万
  • 项目类别:

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一种用于治疗 B 系急性淋巴细胞白血病/淋巴瘤的新型 VpreB1 抗体药物偶联物
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