Laser Interstitial Thermal Therapy for the Treatment of Glioblastoma

项目摘要 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脑瘤。 尽管手术切除一直被证明是有价值的，但有效的手术选择尤其缺乏。 对一些神经胶质瘤患者来说。激光间质热疗(LIT)在临床治疗原发性脑损伤中的应用 肿瘤，但这项技术如何影响肿瘤微环境却知之甚少。我们已经产生了 一种免疫活性的RCAS/NTV-LITT的小鼠模型，其脑内有存活的病变，可用于 描述LITT引起的肿瘤微环境的变化。重要的是，我们有丰富的经验 在小鼠内源性形成高级别胶质瘤的背景下研究肿瘤微环境 模特。我们假设LITT诱导的热损伤可以更多地创造肿瘤微环境 对辅助治疗有反应。在具体目标1中，我们将表征LITT对 通过检查治疗小鼠免疫细胞的涌入和诱导的遗传变化来检测肿瘤微环境 使用纳米线技术。我们还将使用一种小鼠抗PD-1抗体，我们最近展示了 在我们的肿瘤模型中，在新佐剂和佐剂环境中确定其是否对胶质母细胞瘤有效 LITT可提高疗效。而抗PD-1单药治疗胶质母细胞瘤效果不佳 由于肿瘤环境的免疫原性低，其在LITT诱导的免疫细胞浸润背景下的应用 而新抗原的形成可能会对这种类型的癌症产生更大的治疗效果。在具体目标2中， 我们将测定从纳米粒中热释放的阿霉素提高小鼠存活率的能力。 荷瘤小鼠紧随其后。尽管在颅外癌症的临床试验中，热激活的使用 纳米粒子用于治疗脑肿瘤是相当新颖的。全身多柔比星在其他方面也显示出一些好处 小鼠脑癌模型，但其热激活纳米颗粒释放可能允许更局部的传递 并将治疗范围从微小的半影区扩大到肿瘤的浸润性边缘，这是最 胶质母细胞瘤复发的常见来源。随着这些目标的实现，我们将更好地理解如何 肿瘤微环境中的群体免疫细胞对热疗的反应会发生变化。我们会 还要了解热疗后肿瘤微环境中哪些基因程序上调 有可能为我们提供新的治疗靶点，与LITT相结合。这项提案的总体目标是 演示热消融如何影响肿瘤微环境，以及它如何与其他 改善胶质母细胞瘤患者预后的治疗。考虑到现有的治疗方法 调查发现，我们的研究成果临床应用门槛较低。这些研究将作为 为使用LITT治疗脑肿瘤进行更广泛的研究奠定基础。

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.