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Third-party “off the shelf” mature or precursor CAR T cells to prevent or treat malignant relapse after allo HCT

Third-party “off the shelf” mature or precursor CAR T cells to prevent or treat malignant relapse after allo HCT
第三方“现成的”成熟或前体 CAR T 细胞,用于预防或治疗异基因 HCT 后的恶性复发
批准号:
9762469
负责人:
Marcel R M van den Brink
金额:
$68.32万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-01 至 2023-06-30

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中文摘要
翻译
摘要 复发仍然是异基因造血细胞移植后死亡的最重要原因 移植(allo-HCT),在过去几十年中几乎没有进展。嵌合 靶向CD 19的抗原受体(CD 19-汽车)重定向T细胞效应子功能以消除 表达CD 19的白血病和淋巴瘤细胞。我们在临床前研究中发现, 供体来源的CD 19-CAR T细胞可以具有显著的抗淋巴瘤活性, 抗宿主病(GVHD),这一观察结果在临床试验中得到了其他人的证实。我们 发现这是由于CAR-T细胞的耗尽和缺失,可归因于累积的 通过同种异体反应性TCR和CAR两者的信号传导。此外,我们还展示了 在T细胞中缺失内源性TCR和表达CD 19-CAR的可行性 CRISPR技术可以进一步降低这些细胞的潜在同种异体反应性。我们有 还开发了一种体外培养系统,以产生通用的第三方T细胞前体(preT) 其可以被工程化以在胸腺后表达CD 19-CAR以避免负选择。后 在allo-HCT接受者中的过继转移中,这些工程化的preT细胞可以在宿主的 胸腺和发挥抗恶性肿瘤活性而没有GVHD。除了抗恶性肿瘤的潜力, 这些工程化的preT细胞还可以增强免疫重建。基于这些发现 以及过继转移的第三方抗病毒T细胞在allo-HCT受体中的临床功效, 我们假设输注第三方“现成的”成熟或表达CAR的preT细胞, 靶向肿瘤相关抗原的TCR将促进抗恶性肿瘤活性, 增强具有最小或无GVHD的allo-HCT受体的免疫重建。我们建议预- 使用工程化的第三方成熟和preT细胞预防或治疗复发的临床研究 allo-HCT。在目的1中,我们将使用临床前allo-HCT模型来评估抗恶性肿瘤的药物组合物。 活性、GVHD潜力和第三方T细胞的持久性,其内源性TCR已经被 使用CRISPR缺失并且表达(1.1)CD 19-CAR,(1.2)三抗原特异性汽车,或 (1.3)CD 19-CAR/WT-1特异性TCR。在目标2中,我们将研究表达(2.1)的第三方preT细胞 CD 19-CAR,(2.2)CD 19-CAR和细胞因子,或(2.3)CD 19-CAR/WT 1特异性TCR。我们有 已经开发了两项使用供体来源的CD 19-CAR T细胞或第三方的allo-HCT临床试验。 preT细胞,再加上我们在CAR T细胞方面的丰富临床经验,将有助于 翻译拟议的临床前研究,以减少allo-HCT患者的复发, 使用第三方CAR T细胞治疗血液恶性肿瘤。
英文摘要
Abstract Relapse remains the most important cause of mortality after allogeneic hematopoietic cell transplantation (allo-HCT) and little progress has been made in the past decades. Chimeric antigen receptors targeting CD19 (CD19-CARs) redirect T cell effector functions to eliminate CD19-expressing leukemia and lymphoma cells. We found in pre-clinical studies that allogeneic donor-derived CD19-CAR T cells can have significant anti-lymphoma activity with minimal graft- versus-host disease (GVHD), an observation that was confirmed by others in clinical trials. We found that this was due to exhaustion and deletion of CAR-T cells attributable to cumulative signaling through both the alloreactive TCR and the CAR. In addition, we have demonstrated the feasibility of deletion of the endogenous TCR and expression of a CD19-CAR in T cells using CRISPR technology, which could further reduce potential alloreactivity of these cells. We have also developed an in vitro culture system to generate universal third-party T cell precursors (preT) that can be engineered to express CD19-CAR post-thymically to avoid negative selection. Upon adoptive transfer in allo-HCT recipients, these engineered preT cells can mature in the host’s thymus and exert anti-malignancy activity without GVHD. In addition to anti-malignancy potential, these engineered preT cells can also enhance immune reconstitution. Based on these findings and the clinical efficacy of adoptively transferred third party anti-viral T cells in allo-HCT recipients, we hypothesize that infusion of third-party “off-the-shelf” mature or preT cells expressing CARs and TCRs targeted against tumor-associated antigens will promote anti-malignancy activity and enhance immune reconstitution in allo-HCT recipients with minimal or no GVHD. We propose pre- clinical studies with engineered third-party mature and preT cells to prevent or treat relapse after allo-HCT. In Aim 1, we will use pre-clinical allo-HCT models to evaluate the anti-malignancy activity, GVHD potential and persistence of third-party T cells whose endogenous TCR has been deleted using CRISPR and that express (1.1) CD19-CAR, (1.2) triple-antigen-specific CARs, or (1.3) CD19-CAR/WT-1 specific TCR. In Aim 2, we will study third-party preT cells expressing (2.1) a CD19-CAR, (2.2) a CD19-CAR and cytokines, or (2.3) CD19-CAR/WT1 specific TCR. We have already developed two allo-HCT clinical trials with donor-derived CD19-CAR T cells or third-party preT cells, which together with our extensive clinical experience with CAR T cells will facilitate the translation of the proposed preclinical studies to decrease relapse in allo-HCT patients with hematologic malignancies using third party CAR T cells.
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  • 项目类别:
  • 资助金额:
    $106.2万
  • 财政年份:
    2023
  • 负责人:
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    2019
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  • 批准号:
    10179457
  • 项目类别:
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  • 负责人:
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海外基金