Translational Application of Magnetic Hyperthermia Therapy with Adjuvant Therapies for Glioblastoma

磁热疗法与辅助疗法在胶质母细胞瘤中的转化应用

• 批准号: 10308036
• 负责人: Constantinos George Hadjipanayis
• 金额: $ 67.49万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308036
• 关键词: Address; Adjuvant Therapy; Aftercare; Animal Model; Animals; Autopsy; Brain; Brain Neoplasms; Canis familiaris; Cell Death; Clinical; Clinical Research; Clinical Trials; Computer Models; DNA Double Strand Break; Data; Deposition; Dose; Effectiveness; European; Excision; Exposure to; External Beam Radiation Therapy; Finite Element Analysis; Formulation; Foundations; Generations; Glioblastoma; Glioma; Heat shock proteins; Heating; Histopathology; Human; Hyperthermia; Image; Injections; Iron; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Methodology; Modeling; Mus; Nanotechnology; Normal Cell; Normal tissue morphology; Oral Administration; Oryctolagus cuniculus; Patients; Penetration; Pilot Projects; Prognosis; Radiation therapy; Recurrence; Rodent; Safety; Solid; Study of magnetics; Technology; Temperature; Tissues; Toxic effect; Treatment Efficacy; Tumor Debulking; Work; antitumor effect; base; bioluminescence imaging; brain tissue; cancer cell; chemoradiation; chemotherapy; clinical translation; clinically relevant; design; effective therapy; fractionated radiation; hyperthermia treatment; hyperthermia tumor treatment; image guided; imaging modality; improved; innovation; iron oxide nanoparticle; magnetic dipole; magnetic field; nanoparticle delivery; neoplastic cell; radiation effect; safety and feasibility; temozolomide; therapy resistant; tissue injury; tool; translation to humans; translational applications; translational potential; treatment planning; treatment response; tumor; tumor microenvironment

Project Summary/Abstract Glioblastoma (GBM) remains a fatal brain cancer for which there is no cure. Maximal safe tumor resection combined with adjuvant therapies such as fractionated external beam radiation therapy (RT) and temozolomide (TMZ) chemotherapy, known as chemoradiation (CRT), has provided the greatest benefit to GBM patients. However, local recurrence occurs in most patients due to invasive therapy-resistant infiltrating cancer cells at the tumor margin. Magnetic hyperthermia therapy (MHT) is a powerful nanotechnology-based treatment that may enhance the effects of CRT. MHT consists of local heat generation in the tumor region through direct delivery of magnetic iron-oxide nanoparticles (MIONPs) that are activated by exposure to an external alternating magnetic field (AMF) that is safe to normal cells. The AMF interacts with the magnetic dipoles of the MIONPs to generate local heat and hyperthermia. Human clinical trials have demonstrated overall survival benefits of MHT with fractionated RT in recurrent GBM resulting in European approval. Current MHT strategies, however, require high concentrations of nontargeted MIONPs (>100 mg/ml; 50-100mg Fe/g of tumor) delivered by injection with leakback and without image-guided control of energy deposition. As a result, normal tissue injury limits MHT effectiveness and treatment of the infiltrative tumor margins is poorly defined, which compromises MHT efficacy. Our proposal is designed to address these challenges and optimize the translational potential for enhanced MHT of GBM in combination with CRT using both small and large animal models, with clinical proof-of-concept demonstration in spontaneous canine gliomas. We have recently completed a pilot study in spontaneous canine gliomas demonstrating feasibility and safety of image-guided MIONP delivery alone. We hypothesize that image-guided MHT will enhance CRT of GBM. Key innovations of our proposal are to: 1) evaluate the enhancement of CRT by MHT in mouse GBM models with an innovative proprietary MIONP formulation that requires 20-fold lower Fe concentration in tumors for more effective treatment than current approved MIONPs; 2) optimize image-guided MIONP delivery and MHT treatment planning with computational modelling in a rabbit brain tumor model; 3) enhance thermal treatment at the infiltrative tumor margins by controlling power deposition with innovative AMF power application that will also limit off target heating; and, 4) complete a clinically relevant proof-of-concept study of our MHT approach in a spontaneous canine glioma model. We have Preliminary Data that demonstrate intracranial hyperthermia with a 3-fold increase in TMZ concentration within GBM tumors, leading to a robust antitumor effect with increased survival after MHT + CRT in a therapy-resistant rodent glioma model. Overall, this interdisciplinary work will provide a solid foundation for meaningful clinical translation of MHT with CRT for treatment of GBM. Imaging methods that correlate tumor heat distribution after MHT will be developed for translation to human patients.

项目概要/摘要 胶质母细胞瘤（GBM）仍然是一种致命的脑癌，无法治愈。最大限度安全切除肿瘤 与辅助治疗相结合，例如分段外照射放射治疗 (RT) 和替莫唑胺 (TMZ) 化疗，也称为放化疗 (CRT)，为 GBM 患者提供了最大的益处。 然而，由于侵入性治疗耐药的浸润癌细胞，大多数患者会出现局部复发。 肿瘤边缘。磁热疗 (MHT) 是一种基于纳米技术的强大治疗方法， 可以增强CRT的效果。 MHT 通过直接在肿瘤区域产生局部热量 递送磁性氧化铁纳米颗粒 (MIONP)，通过暴露于外部交流电而激活 对正常细胞安全的磁场（AMF）。 AMF 与 MIONP 的磁偶极子相互作用 产生局部热量和高温。人体临床试验已证明 MHT 的总体生存益处 复发性 GBM 的分次放疗获得欧洲批准。然而，当前的 MHT 策略 需要高浓度的非靶向 MIONP（>100 mg/ml；50-100mg Fe/g 肿瘤） 具有回漏的注射，并且没有图像引导的能量沉积控制。结果，正常组织 损伤限制了 MHT 的有效性，并且浸润性肿瘤边缘的治疗定义不明确，这 损害 MHT 功效。我们的建议旨在应对这些挑战并优化转化 使用小型和大型动物模型结合 CRT 增强 GBM MHT 的潜力， 自发性犬神经胶质瘤的临床概念验证演示。我们最近完成了一项试点研究 在自发性犬神经胶质瘤中证明了单独使用图像引导 MIONP 递送的可行性和安全性。我们 假设图像引导 MHT 将增强 GBM 的 CRT。我们提案的主要创新点是：1） 使用创新的专有 MIONP 评估 MHT 在小鼠 GBM 模型中对 CRT 的增强作用 与现有制剂相比，肿瘤中铁浓度降低 20 倍才能更有效地治疗 批准的 MIONP； 2) 通过计算优化图像引导的 MIONP 输送和 MHT 治疗计划 兔脑肿瘤模型建模； 3）通过以下方式增强浸润性肿瘤边缘的热处理 通过创新的 AMF 功率应用控制功率沉积，这也将限制目标加热；以及，4) 完成我们的 MHT 方法治疗自发性犬神经胶质瘤的临床相关概念验证研究 模型。我们的初步数据表明 TMZ 增加 3 倍可导致颅内高温 GBM 肿瘤内的浓度，导致强大的抗肿瘤作用，并提高 MHT + CRT 后的生存率 在治疗耐药的啮齿动物神经胶质瘤模型中。总体而言，这项跨学科工作将为 MHT 联合 CRT 治疗 GBM 的有意义的临床转化。与肿瘤相关的成像方法 MHT 后的热量分布将被开发用于人类患者。