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 靶向CD 19的嵌合抗原受体T细胞(CAR-Ts)已经彻底改变了细胞免疫疗法, 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性淋巴瘤 白血病(B-ALL)。尽管完全缓解率很高,复发率,其中50%在第一年内, 仍然是一个关键的挑战,突出了对新型CAR-T细胞产品的需求。复发的两种模式是 观察到:(i)由靶抗原丢失引起的抗原阴性复发和(ii)抗原阳性复发, 是由CAR-T缺乏持久性或功能丧失介导的。商业CD 19 CAR-T采用 无论是CD 28或4-1BB共刺激结构域,然而,一种新的OX-40结构域已经显示出促进 持久性、细胞毒性和减少疲劳。最后,越来越多的证据表明, CAR-T产品中的记忆T细胞表型与更持久的应答相关。施奈德等al 开发了具有OX-40共刺激结构域的三特异性CD 19、CD 20、CD 22靶向CAR-T, 与CD 19 CAR-T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 内部生产的三特异性CAR-T的结果,并证实了其特异性、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 商业CD 19 CAR-T通过首次在人体内部生产的三特异性CAR-T与OX- 40共刺激结构域用于复发性、难治性B细胞恶性肿瘤。这些三特异性CAR-T是 在俄亥俄州州立大学细胞治疗实验室使用CliniMACS Prodigy设备通过 6-一天的制造过程,允许注入干样记忆CAR-T。我们假设 三特异性CART将(i)降低由抗原阴性克隆逃逸介导的复发风险;(ii)增强免疫应答;(iii)增强免疫应答。 CAR-T的持久性将转化为更深入和更持久的临床反应。为了解决这个问题, 我们提出两个目标。在目标1中,我们的目标是进行首次人体I期试验, 复发性/难治性B-NHL、B-ALL、B-幼淋巴细胞白血病和慢性 淋巴细胞白血病主要终点是三特异性CAR-T沿着的可行性、安全性以及建立 II期推荐剂量次要终点是疗效和缓解持续时间。在目标2中,我们旨在 确定对三特异性CAR-T的功效和抗性的关键机制。具体而言,我们计划评估:(i) CAR-Ts的持续性及其与完全缓解率、缓解持续时间以及 不良事件的发生率和严重程度;(ii)受损的免疫表型和转录特征 使用最先进的高维光谱流式细胞术检测CAR-T和其他单核细胞的功能 和CITE-sequencing。 在这个项目完成后,我们的工作将建立内部生产三特异性的可行性, CAR-Ts并提供了对复发和疗效机制的见解。

项目成果

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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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