A novel NKG2D-specific BiTE cancer immunotherapy

一种新型 NKG2D 特异性 BiTE 癌症免疫疗法

• 批准号: 8974814
• 负责人: Charles L. Sentman
• 金额: $ 33.62万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974814
• 关键词: Address; Autologous Tumor Cell; Binding; CD3 Antigens; Cancer Patient; Cell physiology; Cells; Clinical; Critical Pathways; Data; Development; Development Plans; Dose; Environment; Excision; Fc Receptor; Health; Hematologic Neoplasms; Human; Human Resources; IGL@ gene cluster; Immune; Immune system; Immunosuppressive Agents; Immunotherapy; Lead; Ligands; Link; Liquid substance; Location; Lymphoma; Malignant Neoplasms; Modeling; Mus; Myelogenous; Normal Cell; Patients; Phase; Positioning Attribute; Primary Neoplasm; Proteins; Regulatory T-Lymphocyte; Site; Solid; Solid Neoplasm; Species Specificity; Study models; Suppressor-Effector T-Lymphocytes; System; T-Lymphocyte; Therapeutic; Toxic effect; Tumor Immunity; Work; cancer immunotherapy; design; experience; extracellular; immune clearance; indium arsenide; melanoma; neoplastic cell; novel; novel therapeutics; pre-clinical; research clinical testing; success; trafficking; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): This proposal will develop a novel cancer immunotherapy that uses scFv-NKG2D to treat liquid and solid tumors. The scFv-NKG2D is a Bispecific T cell Engager (also referred to as a BiTE) that uses an anti-CD3 scFv linked to the extracellular portion (EC) of NKG2D to engage T cells with NKG2D ligand+ tumor cells. BiTE molecules with this design do not activate T cells until they bind to ligand+ tumor cells. This molecule lacks an Fc portion so it cannot interact with Fc receptors, which reduces off-target effects. NKG2D ligands are expressed on many types of tumor cells but rarely normal cells, which provide a relatively specific way to target many kinds of tumor cells. In addition, data indicate that T regulatory (Treg) cells and myeloid-derived suppressor cells (MDSCs) can express NKG2D ligands within the tumor microenvironment, so that by targeting NKG2D ligands it may also lead to elimination of these immune suppressive cells and promote anti-tumor immunity. We have developed both various murine and human versions of scFv-NKG2D that bind to murine or human CD3 and murine or human NKG2D ligands. Because of the species specificity of these molecules, we can use these other versions as control proteins. We will determine efficacy of scFv-NKG2D with primary human T cells and autologous tumor cells, and we will determine ways to enhance efficacy by increasing T cell function and trafficking. This proposal has three specific aims: Aim 1: To determine the efficacy of scFv-NKG2D therapy against solid and hematological tumors. Aim 2: To determine efficacy against human tumors and off-target effects of scFv-NKG2D therapy. Aim 3: To enhance the efficacy of scFv-NKG2D therapy by removal of immunosuppressive mechanisms. We have obtained preliminary evidence for efficacy of scFv-NKG2D against solid and liquid types of tumors, and data indicate that merely 5¿g i.v. significantly enhances survival. We have personnel that have extensive experience working with NKG2D, murine tumor models, and studying immune mechanisms. This immunotherapy approach has the potential to be beneficial against a wide variety of tumors because of the broad expression of NKG2D ligands on many tumors. Because it also targets immunosuppressive cells within the tumor microenvironment, scFv-NKG2D treatment may prove more efficacious than approaches that only target the tumor cells themselves. We have an expert team of clinical and scientific collaborators involved in these studies, so we will be ina strong position to create a development plan for phase I clinical testing.

描述（由申请人提供）：该提案将开发一种新型癌症免疫疗法，使用 scFv-NKG2D 治疗液体和实体瘤。 scFv-NKG2D 是一种双特异性 T 细胞接合器（也称为 BiTE），它使用与 NKG2D 的细胞外部分 (EC) 连接的抗 CD3 scFv，使 T 细胞与 NKG2D 配体+肿瘤细胞接合。采用这种设计的 BiTE 分子在与配体+肿瘤细胞结合之前不会激活 T 细胞。该分子缺乏 Fc 部分，因此无法与 Fc 受体相互作用，从而减少脱靶效应。 NKG2D配体在多种肿瘤细胞上表达，但在正常细胞上很少表达，这为靶向多种肿瘤细胞提供了相对特异的途径。此外，数据表明，调节性T细胞（Treg）和髓源性抑制细胞（MDSC）可以在肿瘤微环境中表达NKG2D配体，因此通过靶向NKG2D配体也可能导致这些免疫抑制细胞的消除，促进抗肿瘤免疫。我们开发了多种鼠类和人类版本的 scFv-NKG2D，可与鼠类或人 CD3 以及鼠类或人 NKG2D 配体结合。由于这些分子的物种特异性，我们可以使用这些其他版本作为对照蛋白。我们将确定 scFv-NKG2D 对原代人类 T 细胞和自体肿瘤细胞的功效，并且我们将确定通过增加 T 细胞功能和运输来增强功效的方法。 该提案具有三个具体目标： 目标 1：确定 scFv-NKG2D 疗法对实体瘤和血液肿瘤的疗效。目标 2：确定 scFv-NKG2D 疗法对人类肿瘤的功效和脱靶效应。目标 3：通过消除免疫抑制机制来增强 scFv-NKG2D 疗法的功效。 我们已经获得了 scFv-NKG2D 对固体和液体类型肿瘤功效的初步证据，数据表明仅 5μg 静脉注射即可。显着提高生存率。我们的人员在 NKG2D、鼠肿瘤模型和研究免疫机制方面拥有丰富的经验。由于 NKG2D 配体在许多肿瘤上广泛表达，这种免疫疗法有可能对多种肿瘤有益。由于 scFv-NKG2D 还针对肿瘤微环境中的免疫抑制细胞，因此 scFv-NKG2D 治疗可能比仅针对肿瘤细胞本身的方法更有效。我们拥有一支由临床和科学合作者组成的专家团队参与这些研究，因此我们将处于有利地位，可以制定 I 期临床测试的开发计划。