Laser Interstitial Thermal Therapy for the Treatment of Glioblastoma

项目摘要 可用于治疗胶质母细胞瘤的选择非常有限，胶质母细胞瘤是人类最常见的原发性脑肿瘤。 有效的手术选择是特别缺乏，虽然切除已被证明是一贯的价值 对于一些神经胶质瘤患者来说。激光间质热疗（LITT）是临床上用于治疗原发性脑 肿瘤，但这项技术如何影响肿瘤微环境知之甚少。我们已经生成 免疫活性RCAS/Ntv-具有可存活脑损伤的LITT小鼠模型，其可用于 表征LITT诱导的肿瘤微环境变化。重要的是，我们拥有丰富的经验 研究小鼠内源性高级别胶质瘤的肿瘤微环境 模型我们假设LITT诱导的热损伤可以创造一个肿瘤微环境， 对辅助治疗有反应。在具体目标1中，我们将描述LITT对 通过检查治疗小鼠的免疫细胞流入和诱导的遗传变化来观察肿瘤微环境 使用NanoString技术。我们还将使用鼠抗PD-1抗体，我们最近已经证明， 在我们的肿瘤模型中，在新辅助治疗和辅助治疗环境中有效对抗胶质母细胞瘤，以确定其 通过LITT可以增强功效。虽然用于胶质母细胞瘤的抗PD-1单药治疗由于以下原因而无效： 对于低免疫原性的肿瘤环境，其在LITT诱导的免疫细胞浸润的背景下的用途 并且新抗原形成可导致针对这种类型的癌症的更大治疗益处。在具体目标2中， 我们将确定从纳米颗粒中热释放阿霉素的能力， LITT后的荷瘤小鼠。尽管在颅外癌症的临床试验中， 用于治疗脑肿瘤的纳米颗粒是相当新颖的。全身多柔比星在其他治疗中显示出一定的益处。 小鼠脑癌模型，但其热激活纳米颗粒释放可能允许更多的局部递送 并将治疗范围扩大到LITT半暗带以外的肿瘤浸润边缘，这是迄今为止 胶质母细胞瘤复发的常见原因。随着这些目标的实现，我们将更好地了解如何 肿瘤微环境中的免疫细胞群响应热疗法而改变。我们将 我也了解在热疗后肿瘤微环境中哪些遗传程序被上调 潜在地为我们提供了新的治疗靶点来将联合收割机与LITT结合。本提案的总体目标是 演示热消融如何影响肿瘤微环境，以及如何与其他 改善胶质母细胞瘤患者预后的治疗。考虑到治疗方法的可用性 研究结果的临床应用门槛较低。这些研究将作为 为更广泛地研究使用LITT治疗脑肿瘤奠定了基础。

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.