Leveraging MR-Guided Focused Ultrasound to Potentiate Immunotherapy for GBM

通过检查点封锁进行免疫治疗可能是胶质母细胞瘤(GBM)的一个有吸引力的选择， 疾病的治疗选择有限。检查点免疫治疗在其他癌症中的临床反应 设置通常依赖于预先存在的免疫渗透。然而，胶质母细胞瘤通常较差。 被效应器免疫细胞渗透。因此，辅助途径的翻译可以增强T细胞的渗透 和/或解除免疫抑制的肿瘤微环境可以极大地扩大GBM患者的人数 对免疫疗法表现出持久的反应。为了实现这一目标，我们假设 聚焦超声(FUS)的GBM微环境，应用于旨在诱导部分 热消融或微泡空化可以刺激免疫反应，这两种反应都是内在的 治疗和与可翻译免疫疗法的协同作用。事实上，我们对黑色素瘤的初步研究表明 应用FUS可通过运输激活的淋巴细胞来控制肿瘤生长并提高存活率 从淋巴结到肿瘤。 这项提议由两个具体目标组成，这两个目标将用于定义固有的和 通过对肿瘤应用不同的FUS能量方案而引发的适应性免疫反应，识别 肿瘤免疫障碍，并确定更有效地结合FUS能量的治疗方案 辅助性免疫疗法治疗基底膜的方案。具体目标1将是确定 在影响激活中所涉及的顺序步骤的离散因素上选择FUS能量机制， 树突状细胞(DC)在肿瘤微环境中的扩增和募集。具体目标2将是 评估选定的FUS方案促进T细胞向外转运和外渗的能力 GBM肿瘤微环境，并询问假说驱动的药物选择是否促进了贩运 可以增强T细胞在肿瘤中的存在和持久性。这将使我们能够了解 通过接种疫苗或过继转移后扩大T细胞的途径。展望未来，这将是一个关键的 在优化FUS与抗肿瘤免疫治疗的结合方面。我们相信，系统和 本文提出的定向治疗方法更有可能成功地治疗患有以下疾病的GBM患者 T细胞浸润有限。

Immunotherapy via checkpoint blockade could be an attractive option for Glioblastoma (GBM), a disease with limited treatment options. A clinical response to checkpoint immunotherapy in other cancer settings is often dependent upon a pre-existing immune infiltrate. However, glioblastoma is commonly poorly infiltrated by effector immune cells. Thus, the translation of adjunct approaches that enhance T-cell infiltration and/or lift the immunosuppressive tumor microenvironment could vastly expand the population of GBM patients exhibiting durable responses to immunotherapy. Toward this goal, we hypothesize that perturbation of the GBM microenvironment with focused ultrasound (FUS), applied in energy regimes designed to elicit partial thermal ablation or microbubble cavitation, can stimulate immunologic responses that are both intrinsically therapeutic and synergistic with translatable immunotherapies. Indeed, our pilot studies in melanoma indicate FUS application can elicit tumor growth control and improved survival via trafficking of activated lymphocytes from lymph nodes to the tumor. This proposal is comprised of 2 specific aims that will serve to define differences in the innate and adaptive immune responses that are elicited by applying different FUS energy regimes to tumors, identify barriers to tumor immunity, and ascertain treatment protocols that more effectively combine FUS energy regimes with adjunct immunotherapies for treating GBM. Specific Aim 1 will be to determine the impact of the selected FUS energy regimes on discrete factors that influence the sequential steps involved in the activation, expansion, and recruitment of dendritic cells (DC) to the tumor microenvironment. Specific Aim 2 will be to assess the ability of selected FUS regimens to promote the trafficking and extravasation of T cells into the GBM tumor microenvironment, and ask whether hypothesis-driven selection of agents that promote trafficking can augment T cell presence and persistence within tumors. This will allow us to understand barriers to access for T cells expanded by vaccination or after adoptive transfer. Going forward, this will be a critical aspect in optimizing the combination of FUS with anti-tumor immunotherapy. We believe the systematic and directed approach proposed here is more likely to lead to successful clinical therapies for GBM patients with limited T cell infiltration.