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（由适用提供）：该提案将开发一种新型的癌症免疫疗法，该癌症使用SCFV-NKG2D治疗液体和实体瘤。 SCFV-NKG2D是一种双特异性T细胞参与者（也称为咬合），它使用与NKG2D的细胞外部分（EC）链接的抗CD3 SCFV，将T细胞与NKG2D配体+肿瘤细胞接合。使用该设计的咬合分子直到与配体+肿瘤细胞结合后才激活T细胞。该分子缺乏FC部分，因此无法与FC接收器相互作用，从而降低了靶向效果。 NKG2D配体在许多类型的肿瘤细胞上表达，但很少有正常细胞，这为靶向多种肿瘤细胞提供了相对特异性的方式。此外，数据表明调节（TREG）细胞和髓样衍生的抑制细胞（MDSC）可以在肿瘤微环境中表达NKG2D配体，因此，通过靶向NKG2D配体，它也可能导致消除这些免疫抑制细胞并促进抗肿瘤免疫疗法。我们已经开发了与鼠或人CD3以及鼠或人类NKG2D配体结合的SCFV-NKG2D的各种鼠和人类版本。由于这些分子的规格特异性，我们可以将这些其他版本用作对照蛋白。我们将通过原代人T细胞和自体肿瘤细胞来确定SCFV-NKG2D的有效性，我们将通过增加T细胞功能和运输来确定提高有效性的方法。该提议具有三个特定的目的：目标1：确定SCFV-NKG2D治疗对固体和血液学肿瘤的有效性。目标2：确定针对人类肿瘤的有效性和SCFV-NKG2D疗法的脱靶作用。目标3：通过去除免疫抑制机制来提高SCFV-NKG2D疗法的有效性。我们已经获得了SCFV-NKG2D对固体和液体类型肿瘤的效率的初步证据，并且数据表明仅5¿gi.v.显着提高了生存。我们的人员在NKG2D，鼠肿瘤模型和研究免疫机制方面具有丰富的经验。这种免疫疗法方法有可能对各种肿瘤有益，因为NKG2D配体在许多肿瘤上的表达广泛。由于它还靶向肿瘤微环境中的免疫抑制细胞，因此SCFV-NKG2D处理可能比仅针对肿瘤细胞本身的方法更有效。我们有一个临床和科学合作者的专家团队参与了这些研究，因此我们将在制定I期临床测试的开发计划中是强大的立场。