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

• 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
• 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

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.

尽管积极的多模式治疗，胶质母细胞瘤（GBM）仍然是无法治愈的癌症，生存率很低 其中包括手术、放射、化疗和肿瘤治疗领域。未能改善结果 GBM 患者强调迫切需要开发新的靶向疗法。双特异性 T 细胞接合器 (BiTE) 蛋白质通过 BiTE 与 T 细胞和肿瘤结合，促进激活的 T 细胞对癌细胞的特异性杀伤 细胞。由于这种疗法对于 GBM 等实体瘤尚处于开发的早期阶段，因此我们的 对肿瘤摄取、药代动力学和作用机制的了解有限，这阻碍了合理的研究 评估 BiTE 的临床研究设计。推进 BiTE 作为治疗 GBM 以及其他疾病的策略 针对实体瘤，我们设计并表征了一种特异性靶向的单链抗体 (scFv) IL13Rα2 是一种细胞表面受体，在 GBM 细胞上表达，但在正常脑细胞上不表达。我们已经生成了 并测试了针对人或鼠 CD3 T 细胞的 BiTE 分子的几种配置。我们的数据表明 IL13Rα2 BiTE i) 特异性结合 GBM 细胞上的人 IL13Rα2，ii) 特异性激活 T 细胞 BiTE 分子与这些表达 IL13Rα2 的 GBM 细胞的结合，iii) 介导 T 细胞依赖性 在 pM 浓度下杀死 GBM 细胞，并且 iv) 显着提高携带同源基因的小鼠的存活率 颅内 GBM 肿瘤。成像数据显示 BiTE 可以穿透血肿瘤屏障，并且 吸引 T 细胞。初步结果还表明，BiTE 作用机制不仅限于直接杀伤 激活的 T 细胞不仅可以影响神经胶质瘤细胞，还可以通过激活其他宿主来影响肿瘤微环境 免疫功能。基于我们可靠的临床前数据，我们假设 (i) GBM 能够系统性地访问 递送的 BiTE 是 T 细胞依赖性过程，并且 (ii) BiTE 主动调节 T 细胞以及其他细胞 宿主免疫反应区室，在临床前产生强大的抗肿瘤治疗反应 GBM 模型。该假设将在三个具体目标中得到检验。 SA1 将调查以下项的依赖性 T 细胞上的 IL13Rα2 BiTE 用于肿瘤进入和保留、肿瘤摄取和生物分布。 SA2 将研究 IL13Rα2 BiTE 启动宿主免疫系统产生持久抗肿瘤免疫力的机制。 在 SA3 中，我们将使用鼠类和人类 GBM 模型开发并确定 BiTE 治疗方案，该方案 随后可以转化为患者的治疗方法。成功完成这些研究后，我们 将获得有关影响 BiTE 抗肿瘤活性因素的知识。这些研究将提供 为未来 IL13Rα2 BiTE 治疗 GBM 的临床应用奠定了坚实的基础，并可广泛推广 适用于其他表达 IL13Rα2 的恶性肿瘤。