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

基本信息

批准号：
10615036
负责人：
TIMOTHY N BULLOCK
金额：
$ 66.22万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615036
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 Immunologic Stimulation Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Infiltration Inflammatory Response Innate Immune Response Institution Ipsilateral Lifting Lymphocytic Infiltrate Macrophage 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 infiltration T cell response T-Cell Activation T-Cell Depletion T-Lymphocyte Testing Therapeutic Therapeutic antibodies Thermal Ablation Therapy Thermometry Translations Treatment Protocols Tumor Immunity Tumor Volume Ultrasonic Therapy adaptive immune response adaptive immunity anti-CTLA4 anti-PD-1 design effector T cell experimental study immune activation immune cell infiltrate immunogenicity improved mechanical energy melanoma mortality neoplasm immunotherapy objective response rate patient prognosis rational design recruit resistance mechanism response synergism tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

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）导致临床结果明显改善。然而，客观反应率仍然很低（10-30％），因为许多患者的T细胞未能渗入转移。这是辅助方法的翻译，以增强T细胞浸润和/或取消免疫抑制作用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的种群为了实现这一目标，我们假设黑色素瘤微环境的扰动聚焦超声（FUS），用于旨在引起热消融（T-FUS）和/或的能量方案微泡空化（M-FUS）可以刺激本质上治疗和与可翻译的免疫疗法协同作用。确实，我们的试点研究表明，即使仅适用于一小部分的肿瘤体积，T形和M-Fus与免疫系统合作以控制黑色素瘤。该提案完成了3个具体目标，这些目标将定义先天性的差异通过将不同的FUS能量状态应用于肿瘤来引起的自适应免疫反应，识别障碍进行肿瘤免疫学和确定更有效地将FUS能量状态与用于治疗转移性黑色素瘤的辅助免疫疗法。特定的目标1将首先描述热和在将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，我们将识别出T形和M-融合的“消融分数”，当结合第一线αPD1免疫疗法用于黑色素瘤，产生了最有效的免疫控制远处的肿瘤。这些消融分数将通过其余的提案进行。具体目标2 将需要确定所选的FUS能量状态使用αPD1对影响的离散因素的影响 T细胞向微环境的激活，扩展和募集涉及的顺序步骤 FUS治疗和远处的肿瘤。反过来，这将有助于我们定义优化的免疫细胞激活方案并了解对T细胞介导的肿瘤控制有益或有害的FUS模式的方面。 AIM 2下的其他研究将评估通过应用FUS引起的自适应抗性的机制在这些选定的能源制度中。这将使我们能够理解补偿性的多样性和强度对FUS的抗炎反应，这将是优化FUS与抗肿瘤免疫疗法。最后，特定的目标3都将确定FUS促进抗体的能力肿瘤的入口并利用先前目的的信息来识别和测试选定的FUS的组合我们假设的治疗中的能量方案和免疫治疗药物将产生最有效的控制传播肿瘤。我们认为，这里提出的高度系统性和指导方法更有可能导致针对T细胞浸润有限的黑色素瘤患者的成功临床疗法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ready for Prime Time? Dendritic Cells in High-Grade Gliomas.

DOI：
10.3390/cancers15112902
发表时间：
2023-05-25
期刊：
Cancers
影响因子：
5.2
作者：
通讯作者：

Sonodynamic therapy: Rapid progress and new opportunities for non-invasive tumor cell killing with sound.

DOI：
10.1016/j.canlet.2022.215592
发表时间：
2022-04-28
期刊：
Cancer letters
影响因子：
9.7
作者：
Nowak KM;Schwartz MR;Breza VR;Price RJ
通讯作者：
Price RJ

Ultrasound-targeted nucleic acid delivery for solid tumor therapy.

DOI：
10.1016/j.jconrel.2021.10.010
发表时间：
2021-11-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Schwartz MR;Debski AC;Price RJ
通讯作者：
Price RJ

Functional intersections between extracellular vesicles and oncolytic therapies.

DOI：
10.1016/j.tips.2021.09.001
发表时间：
2021-11
期刊：
Trends in pharmacological sciences
影响因子：
13.8
作者：
Clark RA;Garman ZG;Price RJ;Sheybani ND
通讯作者：
Sheybani ND

Solid Tumor Treatment via Augmentation of Bioactive C6 Ceramide Levels with Thermally Ablative Focused Ultrasound.

通过热消融聚焦超声提高生物活性 C6 神经酰胺水平来治疗实体瘤。

DOI：
10.1101/2023.03.23.532394
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Thim,EAndrew;Fox,Todd;Deering,Tye;Vass,LukeR;Sheybani,NatashaD;Kester,Mark;Price,RichardJ
通讯作者：
Price,RichardJ