Understanding the Behavior of Novel IL13Ralpha2-directed T cell Engager for GBM

了解新型 IL13Ralpha2 定向 T 细胞接合剂对 GBM 的行为

基本信息

批准号：
10604307
负责人：
Irina V Balyasnikova
金额：
$ 39.38万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604307
关键词：
Address Adult Affect Affinity Animal Model Animals Antibodies Behavior Binding Biodistribution Brain CD3 Antigens Cancer Patient Cell Surface Receptors Cells Clinical Research Clinical Trials Combined Modality Therapy Data Dependence Development Drug Kinetics Effectiveness Engineering Epidermal Growth Factor Receptor Failure Flow Cytometry Foundations Future Genetic Genetic Engineering Glioblastoma Glioma Granzyme Human IL13Ralpha2 IL2 gene Image Immune Immune response Immune system Immunocompetent Immunotherapy Infiltration Investigation Knowledge Knowledge acquisition Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Microscopy Modeling Modification Mus Newly Diagnosed Operative Surgical Procedures Organ Patients Penetration Positron-Emission Tomography Pre-Clinical Model Preclinical Testing Process Proteins Protocols documentation Radiation Reagent Recurrence Research Solid Neoplasm Specificity Survival Rate T-Cell Activation T-Lymphocyte TNF gene Testing Testis Tissues Translating Treatment Protocols Tumor Antibodies Tumor Immunity antibody engineering bi-specific T cell engager blood-brain tumor barrier brain cell cancer cell chemotherapy chimeric antigen receptor T cells clinical application cytotoxicity epidermal growth factor receptor VIII human model immune function immunocytochemistry improved improved outcome in vivo longitudinal positron emission tomography mouse model neoplastic cell new therapeutic target novel perforin phase 1 study pre-clinical rational design treatment response tumor tumor microenvironment uptake

项目摘要

Glioblastoma (GBM) remains incurable cancer with a dismal survival rate despite aggressive multimodal therapy that can include surgery, radiation, chemotherapy, and tumor-treating fields. The failure to improve outcome in GBM patients underscores an urgent need to develop new targeted therapies. Bi-specific T cell engager (BiTEs) proteins promote specific killing of cancer cells by activated T cells via BiTE binding to both T-cells and tumor cells. Because this type of therapy is at an early stage of development for solid tumors such as GBM, our knowledge of tumor uptake, pharmacokinetics, and mechanism of action is limited, which hinders the rational design of clinical studies for evaluating BiTEs. To advance BiTEs as a strategy for treating GBM, as well as other solid tumors, we have engineered and characterized a single-chain antibody (scFv) that specifically targets IL13Rα2, a cell surface receptor that is expressed on GBM cells, but not normal brain cells. We have generated and tested several configurations of BiTE molecules targeting human or murine CD3 T cells. Our data show that the IL13Rα2 BiTE i) binds specifically to human IL13Rα2 on GBM cells, ii) specifically activates T cells upon engagement of the BiTE molecule with these IL13Rα2-expressing GBM cells, iii) mediates T-cell dependent killing of GBM cells at pM concentrations, and iv) significantly improves the survival of mice bearing syngeneic intracranial GBM tumors. Imaging data show that BiTEs penetrate through the blood-tumor barrier and also engage T cells. Preliminary results also suggest that the mechanism of BiTE action is not limited to direct killing of glioma cells by activated T cells but also affects the tumor microenvironment by activating additional host immune function. Based on our robust preclinical data, we hypothesize that (i) GBM access of systemically delivered BiTEs is a T-cell-dependent process, and (ii) BiTEs actively modulate T cell as well as other host immune response compartments, leading to a robust anti-tumor therapeutic response in preclinical GBM models. This hypothesis will be tested in three Specific Aims. SA1 will investigate the dependencies of IL13Rα2 BiTE on T cells for tumor access and retention, tumor uptake, and biodistribution. SA2 will study the mechanism by which IL13Rα2 BiTE primes the host immune system to generate durable anti-tumor immunity. In SA3, we will develop and identify a BiTE treatment regimen using murine and human models of GBM that could subsequently be translated into a therapy for patients. Upon successful completion of these studies, we will acquire knowledge regarding factors that influence BiTE anti-tumor activity. These studies will provide a strong foundation for future clinical application of IL13Rα2 BiTE for GBM treatment and could be broadly applicable to other IL13Rα2-expressing malignancies.

胶质母细胞瘤（GBM）仍然无法治愈的癌症，其生存率目的地侵略性多模式治疗这可能包括手术，放射线，化学疗法和肿瘤治疗领域。无法改善结果 GBM患者强调迫切需要开发新的靶向疗法。双特异性T细胞Endager（叮咬）蛋白质通过咬合通过与T细胞结合而激活的T细胞促进癌细胞的特异性杀死细胞。因为这种类型的疗法正处于诸如GBM之类的实体瘤的早期阶段，所以肿瘤吸收，药代动力学和作用机理的知识有限，这阻碍了理性用于评估叮咬的临床研究设计。促进叮咬作为治疗GBM的策略，以及其他实体瘤，我们已经设计并表征了一种专门针对的单链抗体（SCFV） IL13Rα2，一种在GBM细胞上表达的细胞表面受体，但不是正常的脑细胞。我们已经生成了并测试了针对人或鼠CD3 T细胞的咬合分子的几种构型。我们的数据显示 IL13Rα2咬合I）在GBM细胞上特异性与人IL13Rα2特异性结合，ii）特异性地激活了T细胞将咬合分子与这些表达GBM的EL13Rα2细胞参与，iii）介导T细胞依赖性在PM浓度下杀死GBM细胞，iv）显着提高了轴承同步的小鼠的存活率颅内GBM肿瘤。成像数据表明，叮咬穿过血肿瘤屏障，也是吸引T细胞。初步结果还表明，咬合动作的机制不仅限于直接杀戮激活的T细胞的神经胶质瘤细胞，但也通过激活其他宿主来影响肿瘤微环境免疫功能。基于我们强大的临床前数据，我们假设（i）GBM系统地访问交付的叮咬是一个依赖T细胞的过程，（ii）叮咬积极调节T细胞以及其他宿主免疫响应室，导致临床前的强大抗肿瘤治疗反应 GBM型号。该假设将以三个特定目的进行检验。 SA1将调查 IL13Rα2在T细胞上咬合，以获取和保留，肿瘤摄取和生物分布。 SA2将研究 IL13Rα2咬合宿主免疫系统产生持久抗肿瘤免疫组织化学的机制。在SA3中，我们将使用GBM的鼠和人类模型开发和识别一种咬合治疗方案成功完成这些研究后，我们将获取有关影响咬合抗肿瘤活性的因素的知识。这些研究将提供强大的基础，用于将IL13Rα2咬合在GBM治疗中的未来临床应用，可以广泛地进行适用于其他表达IL13Rα2的恶性肿瘤。