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: 8437514
• 负责人: Charles L. Sentman
• 金额: $ 33.51万
• 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/8437514
• 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; 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; pre-clinical; public health relevance; 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）：本提案将开发一种使用scFv-NKG2D治疗液体和实体肿瘤的新型癌症免疫疗法。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将T细胞与NKG2D配体+肿瘤细胞接合。具有这种设计的BiTE分子在与配体+肿瘤细胞结合之前不会激活T细胞。这种分子缺乏Fc部分，因此它不能与Fc受体相互作用，从而减少脱靶效应。NKG2D配体在许多类型的肿瘤细胞上表达，但很少在正常细胞上表达，这为靶向多种肿瘤细胞提供了相对特异性的途径。此外，有数据表明，T调节性细胞（Treg）和髓源性抑制细胞（MDSCs）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。我们已经开发了多种小鼠和人类版本的scFv-NKG2D，可以结合小鼠或人类CD3和小鼠或人类NKG2D配体。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控制蛋白。我们将确定scFv-NKG2D与原代人T细胞和自体肿瘤细胞的疗效，并确定通过增加T细胞功能和运输来增强疗效的方法。该提案有三个具体目的：目的1：确定scFv-NKG2D治疗实体和血液肿瘤的疗效。目的2：确定scFv-NKG2D治疗对人类肿瘤的疗效和脱靶效应。目的3：通过消除免疫抑制机制来增强scFv-NKG2D治疗的疗效。我们已经获得了scFv-NKG2D对固体和液体类型肿瘤有效的初步证据，数据表明仅5¿g静脉注射即可显着提高生存率。我们拥有在NKG2D、小鼠肿瘤模型和免疫机制研究方面具有丰富经验的人员。由于NKG2D配体在许多肿瘤上广泛表达，这种免疫治疗方法有可能对多种肿瘤有益。因为它也靶向肿瘤微环境中的免疫抑制细胞，scFv-NKG2D治疗可能比仅靶向肿瘤细胞本身的方法更有效。我们有一个由临床和科学合作者组成的专家团队参与这些研究，因此我们将在制定I期临床试验的开发计划方面处于有利地位。