Leveraging MR-Guided Focused Ultrasound to Potentiate Immunotherapy for GBM

利用 MR 引导聚焦超声增强 GBM 免疫治疗

• 批准号: 10020956
• 负责人: TIMOTHY N BULLOCK
• 金额: $ 20.89万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020956
• 关键词: Acoustics; Activated Lymphocyte; Acute; Adaptive Immune System; Adoptive Transfer; Antigens; Biology; Blood; Brain; CCL2 gene; CXCL10 gene; CXCL9 gene; Cells; Clinical; Clinical Trials; Companions; Dendritic Cells; Development; Diagnosis; Disease; Effector Cell; Essential Tremor; Exhibits; Extravasation; Focused Ultrasound; Frequencies; Glioblastoma; Goals; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunotherapy; Integrins; Interferon Type II; Intracranial Neoplasms; Investigation; Lead; Lifting; Malignant Neoplasms; Mechanics; Mediating; Microbubbles; Nature; Patients; Peripheral; Pilot Projects; Population; Pre-Clinical Model; Radiation; Regimen; Rest; Site; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Thermal Ablation Therapy; Translations; Treatment Protocols; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Ultrasonic Therapy; Ultrasonography; Vaccination; Work; adaptive immune response; adaptive immunity; base; blood-brain tumor barrier; cancer immunotherapy; cancer type; checkpoint therapy; chemokine; comparative efficacy; conventional therapy; design; draining lymph node; effector T cell; imaging approach; immune checkpoint blockade; improved; insight; lymph nodes; lymphatic drainage; melanoma; monocyte; neoplasm immunotherapy; novel; novel strategies; outcome forecast; pre-clinical; recruit; response; sound; success; therapy development; trafficking; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

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.

通过检查点阻断的免疫治疗可能是胶质母细胞瘤（GBM）的一个有吸引力的选择， 治疗选择有限的疾病。检查点免疫疗法在其他癌症中的临床反应 设置通常取决于预先存在的免疫浸润。然而，胶质母细胞瘤通常很差， 被效应免疫细胞浸润因此，翻译的辅助方法，增强T细胞浸润 和/或改善免疫抑制肿瘤微环境可以极大地扩大GBM患者群体 表现出对免疫疗法的持久应答。为了实现这一目标，我们假设，扰动的 具有聚焦超声（FUS）的GBM微环境，应用于设计用于引起部分 热消融或微泡空化，可以刺激免疫反应， 治疗性的并且与可转化的免疫疗法协同。事实上，我们在黑色素瘤中的初步研究表明， FUS应用可以通过活化淋巴细胞的运输来引起肿瘤生长控制和改善存活 从淋巴结到肿瘤 这一建议包括两个具体目标，将有助于确定先天和 通过对肿瘤应用不同的FUS能量方案引起的适应性免疫应答， 肿瘤免疫屏障，并确定更有效地结合联合收割机FUS能量的治疗方案 方案与辅助免疫疗法用于治疗GBM。具体目标1是确定 对影响激活中涉及的顺序步骤的离散因素选择的FUS能量状态， 扩增和树突状细胞（DC）向肿瘤微环境的募集。具体目标2将是 评估选择的FUS方案促进T细胞运输和外渗到淋巴细胞中的能力。 GBM肿瘤微环境，并询问是否假设驱动选择促进贩运的药物 可以增加肿瘤内T细胞的存在和持久性。这将使我们能够了解 获得通过接种或过继转移扩增的T细胞。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组合方面。我们认为，系统和 本文提出的定向方法更有可能为GBM患者带来成功的临床治疗， 有限的T细胞浸润。