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。癌症的全球负担在1975年至2000年之间增加了一倍。到2020年，预计它将再次加倍，到2030年将其重新加倍。理想情况下，任何癌症治疗都应有效（杀死癌细胞），靶向（即选择性，以避免杀死健康的细胞），永久性（避免复发和转移），并且负担得起。这项工作的最终目标是满足这些标准。研究描述的是基于嵌合NKG2D（CHNKG2D）受体改性的T细胞疗法的大量工作。该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，从而导致移植物与宿主疾病。 同种异体T细胞通过T细胞受体（TCR）介导该反应。我们已经设计了，并将创建和分析表达靶向受体但未表达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（依赖于自体细胞）转换为基于产品的疗法（可以使用健康捐赠者的单元格在单个位置制造这些疗法）。这种区别对于成本和质量控制至关重要。 CHNKG2D受体杀死肿瘤细胞，并以极好的特异性来显着改变肿瘤微环境。此外，该治疗激活宿主对其他肿瘤抗原的免疫力，这会扩大靶向，并且会使肿瘤变异物出现的可能性降低。最后，修饰的T细胞很快从宿主中消除，但是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，也可以防止未来的肿瘤挑战。 CHNKG2D方法也令人信服，因为它不仅限于单个癌症指示。实际上，所有癌症中有70％可以表达该受体的配体。鼠骨髓瘤，淋巴瘤和卵巢癌模型中的体内数据表现出针对液体和实体瘤的安全性和功效。来自同种异体来源的CHNKG2D靶向T细胞将是用于细胞癌疗法的全新范式的第一个例子。 我们将使用针对TCR-（，TCR-（和CD3（链）（AIM I）靶向的shRNA，我们将证明从原代T细胞中取出TCR的能力。然后，我们将证明我们靶向受体的联合表达和原代人T细胞中TCR的损失（AIM II）（AIM II）（AIM II），产生有希望的治疗平台，可以进行良心发育。 公共卫生相关性：我们能够靶向和杀死液体和固体癌症，并同时训练患者自己的免疫系统，以通过使用单个患者的改良免疫细胞来同样（例如，预防转移性疾病）。该项目旨在将该过程转变为产品，从而大大降低成本，并通过实现健康供体的细胞使用来改善过程控制。