Novel Strategies to Treat Diffuse Midline Glioma with CAR T Cell Therapy

利用 CAR T 细胞疗法治疗弥漫性中线胶质瘤的新策略

基本信息

批准号：
10284722
负责人：
Richard G. Vile
金额：
$ 22.3万
依托单位：
MAYO CLINIC ROCHESTER
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：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284722
关键词：
Adenovirus Vector Affinity Anatomy Antigen Presentation Antigen Receptors Antigen Targeting Antigen-Presenting Cells Antigens B-Lymphocytes Brain Neoplasms Brain Stem CAR T cell therapy CD19 gene CD276 gene CD80 gene Cells Chemosensitization Clinical Combined Modality Therapy Complement Cytolysis DHFR gene Data Dendritic cell activation Diffuse Diffuse intrinsic pontine glioma Disease Engineering Escherichia coli Genetic Engineering Glioma Goals H3 K27M mutation Hematology Immune Immune system Immunocompetent Immunotherapeutic agent Immunotherapy Inflammation Interleukin-12 Licensing Location Mediating Modeling Normal tissue morphology Oncolytic Oncolytic viruses Outcome Patients Production Property Reporting Research Project Grants Safety Signal Transduction Solid Neoplasm Stimulus T cell response T-Lymphocyte TNFRSF5 gene TNFSF5 gene Technology Testing Therapeutic Therapeutic Effect Tissues Toxic effect Translations Tropism Tumor Antigens Up-Regulation Viral Virus Virus Activation cancer therapy chimeric antigen receptor chimeric antigen receptor T cells combinatorial cytokine epidermal growth factor receptor VIII expression vector insight melanoma neoplastic neoplastic cell novel novel strategies oncolysis oncolytic adenovirus oncolytic vector pre-clinical recruit research clinical testing response safety testing subcutaneous tumor tumor microenvironment vector

项目摘要

PROJECT SUMMARY Although chimeric antigen receptor (CAR) T cells have been remarkably successful in the hematologic setting, identification of truly tumor specific antigens for many solid tumor indications has limited broad translation. Two targets have been considered for Diffuse Midline Glioma H3 K27M-mutant tumors (previously Diffuse Intrinsic Pontine Glioma (DIPG)), however as neither are exclusively restricted to neoplastic tissue, safety concerns exist with respect to on-target, off-tumor toxicity. Moreover, ancillary treatment meant to boost CAR T function to overcome a constellation of immune suppressive mechanisms associated with the solid tumor microenvironment also has the potential to exacerbate the problem. Our group has conducted extensive preclinical characterization of oncolytic viruses and has demonstrated them to be a highly effective immunotherapeutic agents for the treatment of cancer. We propose to leverage the tumor tropism of ∆24 oncolytic adenovirus to deliver a CAR target along with CD40L. Our preliminary data indicates that oncolytic Ad∆24-CD40L provides a significant therapeutic advantage in a GL261 glioma model as a monotherapy, and further, can potentiate CD19 CAR T therapy in a proof of concept combination setting against subcutaneous B16-CD19 tumors. The goal of this proposal is to develop a dual therapy approach which builds on direct tumor cell viral oncolysis and CAR T cytolysis, enhanced CAR T cell recruitment/activation by virus-mediated inflammation, and importantly, CD40L-mediated mobilization of endogenous antigen presenting cells, B cells and T cells. We will engineer an oncolytic vector to deliver titratable levels of CD40L using the E. coli DHFR destabilizing domain, and an intracellularly truncated signaling-dead EGFRvIII molecule to be used in conjunction with safety tested EGFRvIII CAR T cells (Aim1). The safety and efficacy of the OV-CAR T approach will be evaluated in a genetically engineered immunocompetent model of DIPG (Aim 2). This project is expected to provide novel insight into how CD40L can mobilize an endogenous B cell and T cell response and support CAR T therapy. Together, we hope to capitalize on the properties of designer oncolytic viruses to more broadly enable the use of CAR T cell therapy in solid tumors, and in particular apply existing safety tested immunotherapies to a devastating and urgent unmet clinical need.

项目概要尽管嵌合抗原受体 (CAR) T 细胞在血液学领域取得了异常成功，针对许多实体瘤适应症的真正肿瘤特异性抗原的鉴定限制了广泛的转化两个。靶点已被考虑用于弥漫性中线胶质瘤 H3 K27M 突变肿瘤（之前为弥漫性内在然而，由于两者都不仅仅局限于肿瘤组织，因此存在安全问题此外，辅助治疗旨在增强 CAR T 功能。克服与实体瘤相关的一系列免疫抑制机制微环境也有可能加剧这一问题，我们的小组对此进行了广泛的研究。溶瘤病毒的临床前表征，并证明它们是一种高效的我们建议利用 Δ24 的肿瘤趋向性来治疗癌症。溶瘤腺病毒与 CD40L 一起传递 CAR 靶标，我们的初步数据表明溶瘤腺病毒具有溶瘤作用。 AdΔ24-CD40L 作为单一疗法在 GL261 神经胶质瘤模型中提供了显着的治疗优势，并且此外，可以在针对皮下注射的概念验证组合环境中增强 CD19 CAR T 疗法 B16-CD19 肿瘤该提案的目标是开发一种基于直接治疗的双重治疗方法。肿瘤细胞病毒溶瘤和 CAR T 细胞溶解，通过病毒介导增强 CAR T 细胞招募/激活炎症，最重要的是 CD40L 介导的内源性抗原呈递细胞、B 细胞的动员我们将设计一种溶瘤载体，以使用大肠杆菌 DHFR 提供可滴定水平的 CD40L。不稳定结构域和细胞内截短的信号传导死亡 EGFRvIII 分子，用于与经过安全性测试的 EGFRvIII CAR T 细胞结合使用 (Aim1) OV-CAR T 的安全性和有效性。该方法将在 DIPG 基因工程免疫活性模型中进行评估（目标 2）。预计将为 CD40L 如何动员内源 B 细胞和 T 细胞反应提供新的见解我们希望共同利用设计的溶瘤病毒的特性来支持 CAR T 疗法。更广泛地使用 CAR T 细胞疗法治疗实体瘤，特别是应用现有的安全性测试了免疫疗法来满足毁灭性且紧迫的未满足的临床需求。