LTBR CARs as next-generation therapies for R/R lymphoma

LTBR CAR 作为 R/R 淋巴瘤的下一代疗法

基本信息

  • 批准号:
    10635791
  • 负责人:
  • 金额:
    $ 83.17万
  • 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:
    2023-04-10 至 2028-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first-line treatment. Chimeric antigen receptor (CAR) T-cells have recently emerged as a curative therapy for relapsed or refractory (R/R) DLBCL. However, only 35% of R/R DLBCL patients treated with CAR T-cells have a durable response, and survival is measured in months for patients who fail to benefit. Improvements in CAR T-cells are urgently required to improve outcomes. Recently, we identified the cell surface lymphotoxin beta receptor (LTBR) as a positive T- cell regulator that enhances CD19 CAR T-cell efficacy in vitro and in vivo. LTBR is typically expressed in a subset of myeloid cells but absent in lymphocytes; however when expressed in T-cells, LTBR induces proinflammatory cytokine release, and improves antigen-specific CAR T- and γδ T-cell responses with no appreciable off-target toxicity. Based on these observations, we hypothesize that LTBR can effectively potentiate anti-tumor activity in R/R lymphoma T-cells, reducing markers of T cell exhaustion and outperforming current FDA-approved CAR-Ts across R/R DLBCL subtypes. In Aim 1, we characterize differences in expression of T-cell differentiation, activation, and exhaustion markers and myeloid populations in 25 treatment-naive and 25 R/R DLBCL patient samples. To understand if LTBR can similarly improve CAR-T response in the R/R context, we will use single- cell profiling and functional assays to test autologous CD19+ cell killing, with and without LTBR. In Aim 2 we will evaluate the impact of DLBCL subtype on CAR T-cell activity by introducing LTBR and CAR T-cells into mice xenotransplanted with multiple germinal center B-cell (GCB) and activated B-cell (ABC) cell lines. Since T-cell activation and kinetics are further influenced by patient tumor burden, we will also investigate the efficacy of LTBR-CAR T-cell therapy in a high tumor burden context and test for durable immune memory after complete tumor regression. Recently, by fusing the intracellular signaling domain of LBTR directly to existing (CD28 and 4-1BB) CARs, we have developed a novel CAR construct with more potent antitumor response. In Aim 3 using comprehensive scanning mutagenesis of the LTBR domain, we will create a library of CAR variants and test their ability to improve tumor killing, resistance to exhaustion and cytokine section. We will also measure changes in T-to-B cell immune synapses and resistance to immunosuppression by myeloid-derived suppressor cells (MDSCs) in the most promising LTBR-CARs. This project is the first to comprehensively characterize T cells states in treatment-naive and R/R DLBCL and evaluate LTBR as a T-cell activating strategy to maximize intrinsic anti-tumor activity in R/R DLBCL. There is substantial potential for our work to serve as a bridge from laboratory studies to clinical trials and to help the 40,000 patients per year with R/R DLBCL and other B-cell NHLs.
项目总结 高达50%的弥漫性大B细胞淋巴瘤(DLBCL)患者在一线治疗后复发。嵌合体 抗原受体(CAR)T细胞最近成为治疗复发或难治性(R/R)的一种有效方法。 DLBCL。然而,接受CAR T细胞治疗的R/R DLBCL患者中只有35%有持久的反应, 未能受益的患者的存活率是以月为单位衡量的。CAR T细胞的改进迫在眉睫 以改善结果。最近,我们发现细胞表面淋巴毒素β受体(LTbR)是一种阳性T细胞。 在体外和体内增强CD19CAR T细胞效能的细胞调节因子。LTbR通常以子集表示 指髓系细胞,但在淋巴细胞中不存在;然而,当在T细胞中表达时,LTbR诱导促炎 释放细胞因子,并改善抗原特异性CAR和γδT细胞反应,没有明显的脱靶现象 毒性。基于这些观察,我们假设LTbR可以有效地增强小鼠体内的抗肿瘤活性。 R/R淋巴瘤T细胞,减少T细胞耗竭的标志物,表现优于目前FDA批准的CART 跨R/R DLBCL子类型。在目标1中,我们描述了T细胞分化表达的差异, 25例初治DLBCL和25例R/R DLBCL患者的激活、衰竭标志物和髓系 样本。为了了解LTbR是否可以类似地改善R/R环境中的CAR-T响应,我们将使用Single-T- 在有无LTbR的情况下,细胞图谱和功能分析测试自体CD19+细胞的杀伤作用。在《目标2》中我们将 通过将LTbR和CAR T细胞导入小鼠体内评价DLBCL亚型对CAR T细胞活性的影响 异种移植多生发中心B细胞(GCB)和活化的B细胞(ABC)细胞系。因为T细胞 激活和动力学进一步受患者肿瘤负担的影响,我们还将研究 高肿瘤负荷环境下的LTbR-CAR-CAR T细胞治疗及完成后对持久免疫记忆的测试 肿瘤消退。最近,通过将LBTR的细胞内信号域直接与现有的(CD28和 4-1BB)CARS,我们开发了一种具有更强抗肿瘤反应的新型CAR结构。在AIM 3中使用 全面扫描LTbR结构域的突变,我们将创建一个CAR变异体文库并测试 提高肿瘤杀伤力、抗疲劳能力和细胞因子分泌能力。我们还将衡量变化 T-B细胞免疫突触与髓系抑制细胞对免疫抑制的抵抗 (MDSCs)在最有前途的LTbR汽车中。该项目是第一个全面描述T细胞特征的项目 在治疗中处于幼稚状态和R/R DLBCL,并评估LTbR作为一种T细胞激活策略以最大化内在 R/R DLBCL的抗肿瘤活性我们的工作有很大的潜力作为实验室之间的桥梁 从研究到临床试验,每年帮助40,000名患有R/R DLBCL和其他B细胞NHL的患者。

项目成果

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Catherine Sibyl Diefenbach其他文献

Catherine Sibyl Diefenbach的其他文献

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{{ truncateString('Catherine Sibyl Diefenbach', 18)}}的其他基金

A prospective evaluation of the gut microbiome as a mediator of lymphoma treatment outcome and systemic immunity
肠道微生物组作为淋巴瘤治疗结果和全身免疫调节因子的前瞻性评估
  • 批准号:
    10419202
  • 财政年份:
    2022
  • 资助金额:
    $ 83.17万
  • 项目类别:
A prospective evaluation of the gut microbiome as a mediator of lymphoma treatment outcome and systemic immunity
肠道微生物组作为淋巴瘤治疗结果和全身免疫调节因子的前瞻性评估
  • 批准号:
    10579302
  • 财政年份:
    2022
  • 资助金额:
    $ 83.17万
  • 项目类别:
A Novel Multimodality Immune Based Platform in Advanced Mycosis Fungoides
一种新型多模态免疫平台治疗晚期蕈样肉芽肿
  • 批准号:
    8843818
  • 财政年份:
    2014
  • 资助金额:
    $ 83.17万
  • 项目类别:
A Novel Multimodality Immune Based Platform in Advanced Mycosis Fungoides
一种新型多模态免疫平台治疗晚期蕈样肉芽肿
  • 批准号:
    8678243
  • 财政年份:
    2014
  • 资助金额:
    $ 83.17万
  • 项目类别:
Protocol Review and Monitoring System
方案审查和监控系统
  • 批准号:
    10609023
  • 财政年份:
    1997
  • 资助金额:
    $ 83.17万
  • 项目类别:

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