TCR-less Targeted T Cells Against Cancer

无 TCR 的靶向 T 细胞抗癌

• 批准号: 8057691
• 负责人: MICHAEL W FANGER
• 金额: $ 39.15万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057691
• 关键词: TCR; less; Targeted; Cells; Against

DESCRIPTION (provided by applicant): This year cancer will become the leading cause of death worldwide. The global burden of cancer doubled between 1975 and 2000. By 2020, it is projected to double again, and to triple by 2030. Ideally, any cancer therapy should be effective (at killing cancerous cells), targeted (i.e. selective, to avoid killing healthy cells), permanent (to avoid relapse and metastasis), and affordable. The ultimate goal of this work is to meet each of these criteria. The studies described build upon a significant body of work on a chimeric NKG2D (chNKG2D) receptor modified T cell therapy. This process will be made into a product through a biotech innovation. This innovation will be applicable to most other targeted cell-based therapies. Allogeneic immune cells will attack the host, causing graft-versus-host disease. Allogeneic T cells mediate this response through the T cell receptor (TCR). We have designed, and will create and analyze a T cell which expresses a targeting receptor but does not express TCR. For any non-TCR-based targeting strategy (e.g. cell based Fv-targeting), this will permit allogeneic therapies, thereby transforming a set of process-based therapies (which rely on autologous cells) to product-based therapies (which could be manufactured at a single location using cells from healthy donors). This distinction is critical to both cost and quality control. The chNKG2D receptor is attractive as it kills tumor cells and significantly alters the tumor microenvironment with excellent specificity. Further, the therapy activates host immunity against other tumor antigens, which broadens targeting and will make it less likely for tumor variants to emerge. Finally, the modified T cells are quickly eliminated from the host, but the induced immune response is durable and protects against future tumor challenge, even in the absence of the modified T cells. The chNKG2D approach is also compelling in that it is not limited to a single cancer indication. In fact, 70% of all cancers may express the ligands for this receptor. In vivo data in murine myeloma, lymphoma, and ovarian cancer models, has demonstrated safety and efficacy against both liquid and solid tumors. ChNKG2D-targeted T cells from allogeneic sources would be the first example of a wholly new paradigm for cellular cancer therapies. We will demonstrate the ability to remove TCR from primary T cells using shRNA targeted to TCR-(, TCR-(, and CD3( chains (Aim I). We will then demonstrate the combined expression of our targeting receptor and loss of TCR in primary human T cells (Aim II), yielding a promising therapeutic platform, ready for preclinical development. PUBLIC HEALTH RELEVANCE: We have been able to target and kill both liquid and solid cancers, and to simultaneously train the patient's own immune system to do likewise (e.g. to prevent metastatic disease) through the use of modified immune cells from individual patients. This project aims to transition this process into a product, thereby dramatically decreasing cost and improving process control by enabling the use of cells from healthy donors.

描述（由申请人提供）：今年癌症将成为全球死亡的主要原因。全球癌症负担在1975年至2000年间翻了一番。到2020年，预计将再翻一番，到2030年将翻三倍。理想情况下，任何癌症治疗都应该是有效的（杀死癌细胞），有针对性的（即选择性的，以避免杀死健康细胞），永久性的（以避免复发和转移）和负担得起的。这项工作的最终目标是满足这些标准中的每一项。所描述的研究建立在嵌合NKG 2D（chNKG 2D）受体修饰的T细胞疗法的大量工作基础上。这一过程将通过生物技术创新制成产品。这项创新将适用于大多数其他靶向细胞疗法。同种异体免疫细胞会攻击宿主，引起移植物抗宿主病。 同种异体T细胞通过T细胞受体（TCR）介导这种应答。我们已经设计并将创建和分析一种表达靶向受体但不表达TCR的T细胞。对于任何基于非TCR的靶向策略（例如，基于细胞的Fv靶向），这将允许同种异体疗法，从而将一组基于过程的疗法（其依赖于自体细胞）转化为基于产品的疗法（其可以使用来自健康供体的细胞在单个位置制造）。这种区别对于成本和质量控制都至关重要。 chNKG 2D受体具有吸引力，因为它可以杀死肿瘤细胞，并以优异的特异性显著改变肿瘤微环境。此外，该疗法激活了针对其他肿瘤抗原的宿主免疫力，这扩大了靶向范围，并使肿瘤变体出现的可能性降低。最后，修饰的T细胞被迅速从宿主中消除，但诱导的免疫应答是持久的，即使在没有修饰的T细胞的情况下，也能抵抗未来的肿瘤攻击。 chNKG 2D方法也是引人注目的，因为它不限于单一的癌症适应症。事实上，70%的癌症可能表达这种受体的配体。在鼠骨髓瘤、淋巴瘤和卵巢癌模型中的体内数据已经证明了对液体和实体肿瘤的安全性和有效性。来自同种异体来源的ChNKG 2D靶向T细胞将是细胞癌症治疗全新范例的第一个例子。 我们将证明使用靶向TCR-α、TCR-α和CD 3 α链的shRNA从原代T细胞中去除TCR的能力（Aim I）。然后，我们将展示我们的靶向受体的组合表达和原代人T细胞中TCR的丢失（Aim II），从而产生一个有前途的治疗平台，为临床前开发做好准备。 公共卫生相关性：我们已经能够靶向和杀死液体和固体癌症，并同时训练患者自身的免疫系统，通过使用来自个体患者的修饰免疫细胞来做同样的事情（例如预防转移性疾病）。该项目旨在将这一过程转化为产品，从而通过使用来自健康供体的细胞来大幅降低成本并改善过程控制。