Translational Application of Magnetic Hyperthermia Therapy with Adjuvant Therapies for Glioblastoma

项目概要/摘要 胶质母细胞瘤（GBM）仍然是一种致命的脑癌，目前尚无治愈方法。最大安全肿瘤切除 联合辅助治疗，如分次体外放射治疗（RT）和替莫唑胺 (TMZ)化学疗法，称为化学放射疗法（CRT），为GBM患者提供了最大的益处。 然而，局部复发发生在大多数患者中，由于侵入性治疗抵抗性浸润癌细胞， 肿瘤边缘磁热疗（MHT）是一种强大的基于纳米技术的治疗方法， 可以增强CRT的效果。MHT包括通过直接加热在肿瘤区域中产生局部热。 磁性氧化铁纳米颗粒（MIONP）的递送，所述磁性氧化铁纳米颗粒（MIONP）通过暴露于外部交变磁场而被激活。 磁场（AMF）对正常细胞安全。AMF与MIONP的磁偶极相互作用， 产生局部热量和体温过高。人类临床试验已经证明了MHT的总体生存益处 复发性GBM的分次RT导致欧洲批准。然而，目前的MHT战略， 需要高浓度的非靶向MIONP（>100 mg/ml; 50- 100 mg Fe/g肿瘤）， 注射具有回漏且没有能量沉积的图像引导控制。结果，正常组织 损伤限制了MHT的有效性，浸润性肿瘤边缘的治疗定义不明确， 损害MHT功效。我们的提案旨在应对这些挑战，并优化翻译 使用小型和大型动物模型联合CRT增强GBM MHT的潜力， 自发性犬神经胶质瘤的临床概念验证。我们最近完成了一项试点研究， 在自发性犬神经胶质瘤中，证实了单独的图像引导的MIONP递送的可行性和安全性。我们 假设图像引导MHT将增强GBM CRT。我们的建议的主要创新是：1） 使用创新的专有MIONP在小鼠GBM模型中评价MHT对CRT的增强作用 与目前的制剂相比，该制剂需要在肿瘤中低20倍的Fe浓度以获得更有效的治疗 批准的MIONP; 2）优化图像引导的MIONP输送和MHT治疗计划， 在兔脑肿瘤模型中建模; 3）通过以下方式增强浸润性肿瘤边缘处的热处理： 利用创新的AMF功率应用控制功率沉积，这也将限制非靶加热;以及4） 完成我们的MHT方法在自发性犬胶质瘤中的临床相关概念验证研究 模型我们有初步的数据表明，颅内高热与TMZ的3倍增加 GBM肿瘤内的浓度，导致MHT + CRT后稳健的抗肿瘤作用和生存期延长 在治疗抗性啮齿动物神经胶质瘤模型中。总的来说，这项跨学科的工作将为以下方面奠定坚实的基础： MHT与CRT治疗GBM的有意义的临床转化。与肿瘤相关的成像方法 将开发MHT后的热分布以用于人类患者。

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.