Laser Interstitial Thermal Therapy for the Treatment of Glioblastoma

激光间质热疗法治疗胶质母细胞瘤

• 批准号: 10285714
• 负责人: Ganesh Rao
• 金额: $ 44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285714
• 关键词: Ablation; Adjuvant; Affect; Aftercare; Biology; Bone Marrow; Brain; Brain Neoplasms; Cell Death; Cells; Clinical; Clinical Trials; Conventional Surgery; Diagnosis; Disease; Doxorubicin; Environment; Excision; Exhibits; FDA approved; Failure; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Human; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunologics; Induced Hyperthermia; Infiltration; Intracranial Neoplasms; Lasers; Lead; Lesion; Local Hyperthermia; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Minority; Modality; Modeling; Mus; Mutation; Necrosis; Neoadjuvant Therapy; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Population; Primary Brain Neoplasms; Procedures; Publishing; Radiation; Recurrence; Resistance; Safety; Site; Source; Survival Rate; T-Lymphocyte; Technology; Therapeutic; Thermal Ablation Therapy; Time; anti-PD-1; anti-PD1 antibodies; blood-brain tumor barrier; cancer type; chemotherapeutic agent; chemotherapy; clinical application; contrast enhanced; effective therapy; experience; immunogenicity; improved; improved outcome; interstitial; macrophage; minimally invasive; mouse model; nano-string; nanoparticle; neoantigens; new therapeutic target; novel; pre-clinical; programmed cell death protein 1; programs; response; targeted treatment; therapeutically effective; tool; tumor; tumor growth; tumor microenvironment

Project Summary Very limited options are available for treating glioblastoma, the most common primary brain tumor in humans. Effective surgical options are particularly lacking, although resection has been shown to consistently be of value for some patients with glioma. Laser interstitial thermal therapy (LITT) is in clinical use for treating primary brain tumors, but how this technology affects the tumor microenvironment is poorly understood. We have generated an immunocompetent RCAS/Ntv-a murine model of LITT with survivable brain lesions that can be used to characterize LITT-induced changes in the tumor microenvironment. Importantly, we have extensive experience studying the tumor microenvironment in the context of endogenously forming, high-grade gliomas in this mouse model. We hypothesize that LITT-induced thermal damage can create a tumor microenvironment more responsive to adjunct therapies. In Specific Aim 1, we will characterize the longitudinal effects of LITT on the tumor microenvironment by examining treated mice for an influx of immune cells and induced genetic changes using NanoString technology. We will also use a murine anti-PD-1 antibody, which we have recently shown to be effective against glioblastoma in our tumor model, in neoadjuvant and adjuvant settings to determine if its efficacy can be enhanced by LITT. While anti-PD-1 monotherapy for glioblastoma has not been efficacious due to the low immunogenicity of the tumor environment, its use in the context of LITT-induced immune cell infiltration and neoantigen formation may lead to greater therapeutic benefits against this type of cancer. In Specific Aim 2, we will determine the ability of thermally-released doxorubicin from nanoparticles to improve survival rates of tumor-bearing mice following LITT. Although in clinical trials for extracranial cancers, the use of heat-activated nanoparticles for treating brain tumors is quite novel. Systemic doxorubicin has shown some benefit in other murine models of brain cancer, but its heat-activated nanoparticle release may permit more localized delivery and extended treatment beyond the LITT penumbra to the infiltrating edge of the tumor, which is the most common source of glioblastoma recurrence. With the completion of these aims, we will better understand how the population immune cells in the tumor microenvironment changes in response to thermal therapy. We will also understand what genetic programs are upregulated in the tumor microenvironment after thermal therapy potentially giving us new therapeutic targets to combine with LITT. The overall goal of this proposal is to demonstrate how thermal ablation affects the tumor microenvironment and how it can be combined with other treatments to improve outcomes for patients with glioblastoma. Given the availability of the treatments being investigated there is a low threshold for the clinical application of our results. These studies will serve as the groundwork for more extensive studies on the use of LITT for the treatment of brain tumors.

项目摘要 可用于治疗胶质母细胞瘤（人类最常见的原发性脑肿瘤）的选择非常有限。 尽管已证明切除始终是有价值的，但尤其缺乏有效的手术选择 对于某些神经胶质瘤患者。激光间质热疗法（LITT）用于治疗原发性大脑 肿瘤，但是该技术如何影响肿瘤微环境的理解很少。我们已经生成了 具有免疫能力的RCAS/NTV-A小鼠模型，可生存的脑病变，可用于 表征Litt诱导的肿瘤微环境变化。重要的是，我们有丰富的经验 在这种小鼠中研究肿瘤微环境的内源性，高级神经胶质瘤的背景下 模型。我们假设LITT诱导的热损伤可能会产生更多的肿瘤微环境 对辅助疗法的反应。在特定目标1中，我们将表征LITT对 肿瘤微环境通过检查治疗的小鼠流入免疫细胞并诱导的遗传变化 使用纳米串技术。我们还将使用鼠抗PD-1抗体，最近我们已经证明了该抗体 在我们的肿瘤模型，新辅助和辅助设置中有效抵抗胶质母细胞瘤，以确定它是否是否 Litt可以增强功效。虽然抗胶质母细胞瘤的抗PD-1单一疗法尚未有效 对于肿瘤环境的低免疫原性，其在LITS诱导的免疫细胞浸润的背景下使用 新抗原形成可能会导致对这种类型的癌症的治疗益处。在特定的目标2中， 我们将确定热释放的阿霉素从纳米颗粒提高生存率的能力 litt之后的肿瘤小鼠。尽管在颅外癌的临床试验中，使用热激活 用于治疗脑肿瘤的纳米颗粒非常新颖。全身性阿霉素在其他方面表现出一些好处 脑癌的鼠模型，但其热激活的纳米颗粒释放可能允许更多的局部递送 并将其扩展到超过litt penumbra以外的肿瘤浸润边缘，这是最多的 胶质母细胞瘤复发的常见来源。随着这些目标的完成，我们将更好地了解 肿瘤微环境中的种群免疫细胞因热治疗而变化。我们将 还了解热治疗后肿瘤微环境中哪些遗传程序上调 有可能为我们提供新的治疗靶标与LITT结合。该提议的总体目标是 证明热消融如何影响肿瘤微环境以及如何与其他环境结合 治疗以改善胶质母细胞瘤患者的预后。考虑到治疗的可用性 研究了我们的结果的临床应用阈值较低。这些研究将作为 关于使用LITT治疗脑肿瘤的基础研究。