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: 9916087
• 负责人: Constantinos George Hadjipanayis
• 金额: $ 70.6万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916087
• 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; 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; outcome forecast; radiation effect; safety and feasibility; temozolomide; therapy resistant; tissue injury; tool; translation to humans; 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.

项目摘要/摘要 胶质母细胞瘤（GBM）仍然是致命的脑癌，无法治愈。最大安全肿瘤切除 结合辅助疗法，例如分离的外束辐射疗法（RT）和替莫唑胺 （TMZ）化学疗法，称为化学放疗（CRT），为GBM患者提供了最大的好处。 但是，由于抗侵入性治疗的浸润性癌细胞，大多数患者发生局部复发 肿瘤边缘。磁性高温治疗（MHT）是一种强大的基于纳米技术的治疗方法 可能会增强CRT的影响。 MHT包括直接在肿瘤区域的局部热量产生 通过暴露于外部交流而激活的磁氧化铁纳米颗粒（MIONPS） 对正常细胞安全的磁场（AMF）。 AMF与Mionps的磁偶极子相互作用 产生局部热量和热疗。人类临床试验表明MHT的总体生存益处 复发性GBM的RT分数导致了欧洲的批准。但是，当前的MHT策略， 需要高浓度的非靶向MIONP（> 100 mg/ml; 50-100mg Fe/g的肿瘤） 注射泄漏，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的有效性和渗透性肿瘤边缘的治疗，定义很差，这 损害了MHT功效。我们的建议旨在应对这些挑战并优化翻译 使用小动物模型和 自发犬神经胶质瘤中的临床概念概念示范。我们最近完成了一项试点研究 在自发的犬胶质瘤中，仅显示图像引导的MIONP递送的可行性和安全性。我们 假设图像引导的MHT将增强GBM的CRT。我们提案的关键创新是：1） 评估具有创新专有MIONP的小鼠GBM模型中MHT对CRT的增强 与电流相比，需要在肿瘤中浓度低20倍的Fe浓度的配方 批准的Mionps； 2）使用计算优化图像引导的MIONP交付和MHT治疗计划 在兔脑肿瘤模型中进行建模； 3）通过 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；而且，4） 在自发犬胶质瘤中完成对MHT方法的临床相关概念验证研究 模型。我们有初步数据证明颅内高温，TMZ增加了3倍 GBM肿瘤内的浓度，导致强大的抗肿瘤作用，MHT + CRT后生存增加 在耐治疗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 使用CRT治疗GBM的MHT有意义的临床翻译。与肿瘤相关的成像方法 MHT后的热分布将开发为人类患者。