Image-guided irreversible electroporation directed CAR T-cell delivery to solid tumors

图像引导不可逆电穿孔引导 CAR T 细胞递送至实体瘤

• 批准号: 10221646
• 负责人: Prasad S. Adusumilli
• 金额: $ 41.08万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221646
• 关键词: 3-Dimensional; Ablation; Address; Adoptive Transfer; Anatomy; Blood Vessels; C57BL/6 Mouse; Cell Death; Cell Therapy; Cell membrane; Cell physiology; Cells; Characteristics; Clinical; Clinical Trials; Coculture Techniques; Computer Simulation; Electroporation; Excision; Extracellular Matrix; Goals; Histology; Image; Immune; Immunofluorescence Immunologic; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Inflammation; Inflammatory; Label; Lymphocyte; MSLN gene; Malignant Neoplasms; Malignant Pleural Effusion; Malignant Pleural Mesothelioma; Malignant mesothelioma; Maps; Mediating; Membrane; Metabolic; Modeling; Monitor; Mus; Operative Surgical Procedures; Patients; Pattern; Penetration; Physiologic pulse; Positron-Emission Tomography; Protocols documentation; Reproducibility; Research Design; Resected; Solid Neoplasm; Specimen; Surface Antigens; Surrogate Markers; T cell therapy; T-Lymphocyte; Techniques; Translating; Translations; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Validation; Work; base; bioluminescence imaging; cancer cell; cancer therapy; cell killing; cellular targeting; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; clinical practice; clinically relevant; comparative; cytotoxic; cytotoxicity; design; electric field; experimental study; fluorodeoxyglucose positron emission tomography; genetically modified cells; image guided; in vivo; innovation; intravenous administration; mesothelin; metabolic imaging; mouse model; neoplasm immunotherapy; novel strategies; overexpression; success; targeted delivery; tool; tumor; tumor ablation; tumor microenvironment; tumor-immune system interactions; uptake

PROJECT ABSTRACT Tumor infiltrating lymphocytes (TILs) can significantly increase the success of immunotherapy. Solid tumors present barriers to TIL penetration and function. Strategies to increase TILs and their function are challenged by the inability to direct the delivery of T cells into solid tumors and a lack of techniques to predict their uptake. Through this proposal, we will develop the use of image-guided irreversible electroporation (IRE) as a novel approach to promote TILs in solid tumors. IRE is clinically used for the treatment of solid tumors by applying microsecond long electric pulses that kill cells through rapid permeabilization of the cell membrane. A unique feature of IRE is that, while killing cells, it spares the extracellular matrix and blood vessels within the treatment region, which is ideal for stimulating local inflammation and promoting TILs. We will investigate our proposed strategy in translational mouse models and in patients with malignant pleural mesothelioma (MPM), which is a solid tumor where a higher ratio of cytotoxic TIL to immunosuppressor cells has already been shown to increase patient survival. In our experiments, we will use chimeric antigen receptor (CAR) T cells that are genetically modified to recognize mesothelin, a cell surface antigen that is overexpressed on mesothelioma cancer cells. Based on prior work by the PIs' team, we rationalize that cell death from IRE: (i) can be imaged using intra-procedural FDG-PET; (ii) can generate an intratumoral chemokine gradient that promotes TILs; and (iii) therefore, FDG-PET guided IRE can serve as a surrogate to both map and drive tumor-targeted CAR T-cell delivery. Furthermore, our strategy of IRE-directed CAR T-cell infiltration can be repeated using electric pulse parameters designed to be cancer cell-targeted/TIL-sparing, thereby augmenting immunotherapeutic efficacy. The long-term goal of our work is to develop image-guided IRE as a platform for predictable, reproducible, and controllable delivery of CAR T cells and other cellular anticancer therapies to solid tumors. In Aim 1, we will create an integrated tumor immune microenvironment map (iTIMM) combining FDG-PET imaging, computer simulations, and quantitative multiplex immunofluorescence histology to develop a tool that will determine T- cell localization in solid tumors treated with IRE. iTIMM will then be used to develop a clinically relevant protocol that, in combination of intravenous administration of T cells, will be used to increase TILs. In Aim 2, we will use dual imaging with PET (cancer cells) and bioluminescence imaging (T cells) to validate IRE pulse parameters to selectively enrich and increase functional CAR T cells within MPM. In Aim 3, we will perform a pilot clinical trial using PET-guided transthoracic IRE of MPM prior to resection to validate the concept of iTIMM and its effect on TILs. The modulation of the tumor microenvironment with image-guided IRE to map and localize T-cell delivery, promoting CAR T cell function, and translational validation of iTIMM presents innovative rational combinations of clinically used techniques and is an ambitious attempt to address a key challenge to solid tumor immunotherapy.

项目摘要 肿瘤浸润淋巴细胞（TILS）可以显着增加免疫疗法的成功。实体瘤 直到渗透和功能的当前障碍。提高til及其功能的策略受到挑战 由于无法将T细胞转移到实体瘤中，并且缺乏预测其摄取的技术。 通过此提案，我们将开发使用图像引导的不可逆电穿孔（IRE）作为新颖的 在实体瘤中促进tils的方法。 IRE在临床上用于治疗实体瘤 微秒长的电脉冲，通过快速透化细胞膜杀死细胞。一个独特的 IRE的特征是，在杀死细胞时，它在治疗中省略了细胞外基质和血管 区域是刺激局部炎症和促进tils的理想选择。我们将调查我们的提议 翻译小鼠模型和恶性胸膜间皮瘤（MPM）的策略，这是一个 实体瘤，其中较高的细胞毒性TIL与免疫抑制剂细胞的比率已经显示为 增加患者的生存。在我们的实验中，我们将使用嵌合抗原受体（CAR）T细胞 经过遗传修饰以识别间皮素，间皮素，这种细胞表面抗原在间皮瘤上过表达 癌细胞。根据PIS团队的先前工作，我们合理化了IRE的细胞死亡：（i）可以成像 使用手术内FDG-PET； （ii）可以产生肿瘤内趋化因子梯度，以促进tils；和 （iii）因此，FDG-PET指导的IRE可以用作地图和驱动肿瘤靶向的t-cell的替代品 送货。此外，我们可以使用电脉冲重复我们的IRE指导的汽车T细胞浸润策略 旨在以癌细胞为靶向/截至的参数，从而增强了免疫治疗功效。 我们工作的长期目标是开发图像引导的IRE，作为可预测，可再现和的平台 可控制的CAR T细胞和其他细胞抗癌疗法可控至实体瘤。在AIM 1中，我们将 创建一个集成的肿瘤免疫微环境图（ITIMM），结合了FDG-PET成像，计算机 模拟和定量多重免疫荧光组织学，以开发一种将确定t-的工具 用IRE处理的实体瘤中的细胞定位。然后，ITIMM将用于开发与临床相关的 将T细胞静脉内给药结合起来的协议将用于增加TIL。在AIM 2中，我们 将使用PET（癌细胞）和生物发光成像（T细胞）进行双重成像来验证IRE脉冲 参数有选择地富集和增加MPM内的功能性CAR T细胞。在AIM 3中，我们将执行 在切除之前，使用PET引导的MPM的PET引导的经胸腔IRE进行试验临床试验，以验证ITIMM的概念 及其对tils的影响。用图像引导的ire映射肿瘤微环境的调节 定位T细胞输送，促进CAR T细胞功能和ITIMM的翻译验证呈现创新 临床使用技术的合理组合，是解决关键挑战的一种雄心勃勃的尝试 实体瘤免疫疗法。