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Novel adoptive transfer therapy for glioma using CAR-transduced Type17 T-cells

使用 CAR 转导的 17 型 T 细胞治疗神经胶质瘤的新型过继转移疗法

基本信息

批准号：
8927697
负责人：
Hideho Okada
金额：
$ 39.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927697
关键词：
Achievement Address Adoptive Cell Transfers Adoptive Transfer Antigen Targeting Antigens Autoantigens Autoimmune Process Autoimmunity Autologous Blood - brain barrier anatomy Brain C57BL/6 Mouse CCL20 gene CCR6 gene CNS autoimmunity CXCL10 gene CXCR3 gene Cells Central Nervous System Neoplasms Cerebrum Clinical Trials Collaborations Data Development Ensure EphA2 Receptor Epidermal Growth Factor Receptor Evaluation Foundations Glioblastoma Glioma Goals Health Homing Human Immune Immune response Immunity Immunization Immunocompromised Host Immunosuppressive Agents In Vitro Infiltration Interleukin-17 Ligands Malignant - descriptor Mediating Modeling Molecular Profiling Mus Neuraxis Patients Phenotype Radiation therapy Reporting Rodent Model Safety Site Solid Neoplasm Specificity T-Lymphocyte Therapeutic Therapeutic Effect Toxic effect Transduction Gene Treatment Efficacy Variant Xenograft Model Xenograft procedure antitumor effect base cell type cellular engineering chemokine chemokine receptor chemotherapy chimeric antigen receptor clinically relevant comparative efficacy cytokine improved in vivo interleukin-22 intravenous administration leukemia neoplastic cell novel overexpression pre-clinical preclinical study receptor expression research clinical testing response trafficking tumor vaccine efficacy vaccine trial vector

项目摘要

DESCRIPTION (provided by applicant): The successful application of adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)-transduced T-cells (CAR-T-cells) in solid tumors, such as GBM, will require improved tumor-homing ability by the T-cells. Recent studies of autoimmune conditions in the central nervous system (CNS) show that interleukin-17 (IL-17)-producing Type17 T-cells, which are reactive to CNS autoantigens, have a higher migratory capability to the CNS parenchyma than other T-cell subpopulations due to their ability to penetrate the blood brain barrier (BBB) via expression of IL-17/IL-22. Moreover, a chemokine receptor, CCR6, on Type17 T-cells allows them to infiltrate the CNS by interacting with its ligand, CCL20. Although the induction of CNS autoimmunity should be avoided, these data led us to hypothesize that Type17 T-cells engineered to direct glioblastoma (GBM) antigens will safely demonstrate superior anti-glioma activity compared with Type1 T-cells. To evaluate our hypothesis in preclinical studies, we will employ both a syngeneic mouse glioma model (Aim 1) and a human xenograft model and ACT with human GBM patient-derived CAR-T-cells (Aim 2). Aim 1: Mouse Type17 T-cells will demonstrate superior in vivo persistence, tumor-homing, and anti-tumor effects without CNS autoimmunity in syngeneic glioma models compared with Type1 T-cells. In our preliminary data, Type17 T-cells showed a more sustained anti-tumor immune response in vitro than did Type1 counterparts. Furthermore, our Type17 T-cells express both CXCR3 and CCR6 and induce glioma cells to produce their cognate ligands, CXCL10 and CCL20, respectively. Based on these data, we hypothesize that Type17 T-cells will demonstrate superior therapeutic efficacy against intra-cerebral gliomas compared with Type1 cells due to their greater in vivo persistence and their ability to traffic to CNS tumors. Using a C57BL/6 mouse syngeneic model, we will determine whether the CXCL10-CXCR3 and CCL20-CCR6 chemokine axes promote Type17 cell infiltration of CNS gliomas. We will also ensure the absence of CNS autoimmunity. Aim 2: Human GBM patient-derived Type17 T-cells transduced with CAR will safely mediate anti-tumor effects against human GBM xenograft in vivo. We will evaluate whether we can propagate Type17 CAR-T cells using GBM patient-derived T-cells, and whether the critical phenotype (e.g., chemokine receptor expression) observed in the syngeneic model in Aim 1 can be recapitulated in human GBM patient-derived Type17 T-cells that are transduced with the CAR. Finally, using immunocompromised NOD/scid/gamma c (-/-) (NSG) mice bearing human GBM patient-derived xenografts in the brain, we will determine whether intravenous (i.e.) administration of human Type17 CAR-T-cells, especially both EGFRvIII- and EphA2-CARs compared with the single antigen-targeting approach, achieves effective and long-lasting therapeutic responses against the human GBM xenografts without causing significant CNS toxicity.

描述（由申请人提供）：使用嵌合抗原受体（CAR）转导的t细胞（CAR- t细胞）在实体肿瘤（如GBM）中成功应用过继细胞转移（ACT），将需要t细胞提高肿瘤归家能力。最近对中枢神经系统（CNS）自身免疫性疾病的研究表明，产生白细胞介素17 （IL-17）的17型t细胞对中枢神经系统自身抗原有反应，由于它们能够通过表达IL-17/IL-22穿透血脑屏障（BBB），因此比其他t细胞亚群具有更高的向中枢神经系统实质迁移的能力。此外，17型t细胞上的趋化因子受体CCR6允许它们通过与其配体CCL20的相互作用渗透到中枢神经系统。虽然中枢神经系统自身免疫的诱导应该避免，但这些数据使我们假设，与1型t细胞相比，17型t细胞工程化引导胶质母细胞瘤（GBM）抗原将安全地表现出更强的抗胶质瘤活性。为了在临床前研究中评估我们的假设，我们将采用同基因小鼠胶质瘤模型（Aim 1）和人类异种移植物模型，并使用人类GBM患者来源的car - t细胞（Aim 2）进行ACT。目的1：在同基因胶质瘤模型中，与1型t细胞相比，小鼠17型t细胞在没有中枢神经系统自身免疫的情况下，将表现出更优越的体内持久性、肿瘤归巢和抗肿瘤作用。在我们的初步数据中，17型t细胞在体外比1型t细胞表现出更持久的抗肿瘤免疫反应。此外，我们的17型t细胞同时表达CXCR3和CCR6，并诱导胶质瘤细胞分别产生其同源配体CXCL10和CCL20。基于这些数据，我们假设17型t细胞对脑内胶质瘤的治疗效果优于1型t细胞，因为它们具有更强的体内持久性和转运到中枢神经系统肿瘤的能力。通过C57BL/6小鼠同基因模型，我们将确定CXCL10-CXCR3和CCL20-CCR6趋化因子轴是否促进CNS胶质瘤的17型细胞浸润。我们还将确保没有中枢神经系统自身免疫。目的2:CAR转导的人GBM患者来源的17型t细胞将在体内安全地介导对人GBM异种移植物的抗肿瘤作用。我们将评估是否可以使用GBM患者衍生的t细胞繁殖17型CAR- t细胞，以及在Aim 1的同基因模型中观察到的关键表型（例如，趋化因子受体表达）是否可以在用CAR转导的GBM患者衍生的17型t细胞中重现。最后，我们将使用免疫功能低下的NOD/scid/ γ c (-/-) （NSG）小鼠，在大脑中植入人GBM患者来源的异种移植物，我们将确定静脉注射（即）人17型car -t细胞，特别是EGFRvIII-和EphA2-CARs，与单一抗原靶向方法相比，是否能在不引起显著中枢神经系统毒性的情况下，对人GBM异种移植物获得有效和持久的治疗反应。