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主要死亡原因。 1975 年至 2000 年间，全球癌症负担增加了一倍。到 2020 年，预计将再增加一倍，到 2030 年将增加两倍。理想情况下，任何癌症治疗都应该有效（杀死癌细胞）、有针对性（即有选择性，以避免杀死癌细胞）健康细胞）、永久（避免复发和转移）且价格实惠。这项工作的最终目标是满足这些标准。所描述的研究建立在嵌合 NKG2D (chNKG2D) 受体修饰 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基于细胞的靶向疗法。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) 介导这种反应。我们已经设计并将创建并分析表达靶向受体但不表达 TCR 的 T 细胞。对于任何非基于 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（依赖于自体细胞）转变为基于产品的疗法（可以生产）在一个位置使用来自健康捐赠者的细胞）。这种区别对于成本和质量控制都至关重要。 chNKG2D 受体很有吸引力，因为它可以杀死肿瘤细胞并以优异的特异性显着改变肿瘤微环境。此外，该疗法激活宿主对其他肿瘤抗原的免疫力，从而扩大了靶向范围，并降低了肿瘤变异出现的可能性。最后，修饰的 T 细胞很快就会从宿主体内消除，但诱导的免疫反应是持久的，即使在没有修饰的 T 细胞的情况下，也能防止未来的肿瘤挑战。 chNKG2D 方法的另一个引人注目之处在于它不限于单一癌症适应症。事实上，70% 的癌症可能表达该受体的配体。小鼠骨髓瘤、淋巴瘤和卵巢癌模型的体内数据已证明对液体和实体瘤的安全性和有效性。来自同种异体来源的 ChNKG2D 靶向 T 细胞将成为细胞癌症治疗全新范例的第一个例子。 我们将展示使用靶向 TCR-(、TCR-( 和 CD3( 链) 的 shRNA 从原代 T 细胞中去除 TCR 的能力（目标 I）。然后，我们将展示我们的靶向受体的组合表达和原代 T 细胞中 TCR 的丢失。人类 T 细胞 (Aim II)，产生了一个有前途的治疗平台，为临床前开发做好了准备。 公共健康相关性：我们已经能够靶向并杀死液体和固体癌症，并通过使用来自个体患者的改良免疫细胞同时训练患者自身的免疫系统以实现同样的目的（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捐赠者的细胞来显着降低成本并改善过程控制。