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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：
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
项目类别：
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

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）已导致临床结果的显著改善。然而,