Focused Ultrasound Regimens that Synergize with Melanoma Immunotherapy

与黑色素瘤免疫疗法协同作用的聚焦超声治疗方案

• 批准号: 10032967
• 负责人: TIMOTHY N BULLOCK
• 金额: $ 67.57万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10032967
• 关键词: Ablation; Affect; Animals; Anti-Inflammatory Agents; Antibodies; Antigens; Attenuated; Bilateral; Biopsy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CSF1R gene; Cells; Characteristics; Clinical; Clinical Trials; Combination immunotherapy; Contralateral; Data; Dendritic cell activation; Dependence; Deposition; Detection; Distal; Distant; Drug Delivery Systems; Exhibits; Favorable Clinical Outcome; Focused Ultrasound; Focused Ultrasound Therapy; Foundations; Gene Expression Profile; Genes; Goals; Growth; Human Characteristics; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammatory Response; Institution; Ipsilateral; Lead; Lifting; Lymphocytic Infiltrate; Mammary Neoplasms; Mechanics; Mediating; Metastatic Melanoma; Microbubbles; Modality; Modeling; Mus; Myeloid Cells; Neoplasm Metastasis; Outcome; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Population; Primary Neoplasm; Protocols documentation; Regimen; Regulatory T-Lymphocyte; Resistance; Rest; Role; Sampling; System; Systemic disease; T cell response; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Therapeutic antibodies; Thermal Ablation Therapy; Thermometry; Translations; Treatment Protocols; Tumor Immunity; Tumor Volume; Tumor-infiltrating immune cells; Ultrasonic Therapy; adaptive immune response; adaptive immunity; anti-CTLA4; anti-PD-1; base; design; effector T cell; experimental study; immune activation; immunogenicity; improved; macrophage; melanoma; mortality; neoplasm immunotherapy; objective response rate; outcome forecast; recruit; resistance mechanism; response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Immunotherapies (ITx) for melanoma have led to marked improvements in clinical outcomes. However, objective response rates remain quite low (10-30%) because T-cells fail to infiltrate metastases in many patients. Thus, the translation of adjunct approaches that enhance T-cell infiltration and/or lift the immunosuppressive tumor microenvironment could vastly expand the population of melanoma patients exhibiting durable responses to immunotherapy. Toward this goal, we hypothesize that perturbation of the melanoma microenvironment with focused ultrasound (FUS), applied in energy regimens designed to elicit thermal ablation (T-FUS) and/or microbubble cavitation (M-FUS), can stimulate immunologic responses that are both intrinsically therapeutic and synergistic with translatable immunotherapies. Indeed, our pilot studies indicate that, even when applied to only a small fraction of tumor volume, both T-FUS and M-FUS cooperate with the immune system to control melanoma. This proposal is comprised of 3 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 metastatic melanoma. Specific Aim 1 will first characterize thermal and mechanical energy deposition generated during the application of T-FUS and M-FUS to B16F10 melanoma. Then, using bilateral melanoma tumor models, we will identify T-FUS and M-FUS “ablation fractions” that, when combined with first line αPD1 immunotherapy for melanoma, yield most efficacious immunological control of a distant tumor. These ablation fractions will be carried forward through the rest of the proposal. Specific Aim 2 will entail determining the impact of the selected FUS energy regimes with αPD1 on discrete factors that influence the sequential steps involved in the activation, expansion, and recruitment of T cells to the microenvironments of FUS-treated and distant tumors. In turn, this will help us define optimized protocols for immune cell activation and understand aspects of FUS modalities that are beneficial or detrimental to T cell-mediated tumor control. Additional studies under Aim 2 will assess the mechanisms of adaptive resistance elicited by application of FUS in these selected energy regimes. This will allow us to understand the diversity and intensity of compensatory anti-inflammatory responses to FUS, which will be a critical aspect in optimizing the combination of FUS with anti-tumor immunotherapy. Finally, Specific Aim 3 will both ascertain the ability of FUS to promote antibody entrance to tumor and utilize information from previous aims to identify and test combinations of selected FUS energy regimens and immunotherapeutic drugs in treatments that we hypothesize will yield most effective control of disseminated tumors. We believe the highly systematic and directed approach proposed here is more likely to lead to successful clinical therapies for melanoma patients with limited T cell infiltration.

黑色素瘤的免疫疗法 (ITx) 显着改善了临床结果。然而， 客观缓解率仍然相当低（10-30%），因为许多患者的 T 细胞无法浸润转移灶。 因此，增强 T 细胞浸润和/或解除免疫抑制的辅助方法的转化 肿瘤微环境可以极大地扩大表现出持久反应的黑色素瘤患者群体 到免疫治疗。为了实现这一目标，我们假设黑色素瘤微环境的扰动 聚焦超声 (FUS)，应用于旨在引发热消融 (T-FUS) 的能量疗法和/或 微泡空化（M-FUS）可以刺激免疫反应，这既具有内在的治疗作用，又具有 与可转化免疫疗法具有协同作用。事实上，我们的试点研究表明，即使仅应用于 肿瘤体积的一小部分，T-FUS和M-FUS都与免疫系统配合来控制 黑色素瘤。 该提案由 3 个具体目标组成，这些目标将有助于定义先天和 通过对肿瘤应用不同的 FUS 能量方案而引发适应性免疫反应，识别障碍 肿瘤免疫，并确定更有效地将 FUS 能量方案与 用于治疗转移性黑色素瘤的辅助免疫疗法。具体目标 1 将首先表征热和 将 T-FUS 和 M-FUS 应用于 B16F10 黑色素瘤期间产生的机械能沉积。 然后，使用双侧黑色素瘤肿瘤模型，我们将确定 T-FUS 和 M-FUS“消融分数”，当 与黑色素瘤的一线 αPD1 免疫疗法相结合，产生最有效的免疫控制 远处的肿瘤。这些消融部分将在提案的其余部分继续进行。具体目标2 将需要确定选定的 FUS 能量状态与 αPD1 对影响离散因素的影响 T 细胞激活、扩增和招募到微环境中所涉及的连续步骤 FUS 治疗的肿瘤和远处的肿瘤。反过来，这将帮助我们定义免疫细胞激活的优化方案 并了解 FUS 模式对 T 细胞介导的肿瘤控制有益或有害的方面。 目标 2 下的其他研究将评估 FUS 的应用引起的适应性抵抗机制 在这些选定的能源制度中。这将使我们了解补偿的多样性和强度 FUS 的抗炎反应，这将是优化 FUS 与 FUS 组合的一个关键方面 抗肿瘤免疫治疗。最后，具体目标 3 将确定 FUS 促进抗体的能力 进入肿瘤并利用先前目标的信息来识别和测试所选 FUS 的组合 我们假设治疗中的能量疗法和免疫治疗药物将产生最有效的控制 播散性肿瘤。我们相信这里提出的高度系统化和定向的方法更有可能 为 T 细胞浸润有限的黑色素瘤患者带来成功的临床治疗。