Novel Strategies to Broaden the Impact of HIFU Therapy in Cancer Management

扩大 HIFU 治疗在癌症治疗中影响的新策略

• 批准号: 7511449
• 负责人: PEI ZHONG
• 金额: $ 21.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7511449
• 关键词: Adjuvant; Adjuvant Therapy; Amputation; Animal Model; Animals; Antigen-Presenting Cells; Antigens; CD3 Antigens; CD4 Positive T Lymphocytes; Cancer Patient; Chest wall structure; Classification; Clinical Trials; Colon Adenocarcinoma; Control Groups; Cytolysis; Dendritic Cells; Diagnostic Neoplasm Staging; Distant Metastasis; Effectiveness; Excision; Exhibits; Focused Ultrasound Therapy; Foundations; Future; Granulocyte-Macrophage Colony-Stimulating Factor; Immune response; Immunotherapeutic agent; In Vitro; Infiltration; Injection of therapeutic agent; Invasive; Investigation; Lead; Light; Localized; Malignant Neoplasms; Mechanics; Methods; Modality; Modeling; Multimodal Imaging; Mus; Necrosis; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Outpatients; Pancreatic carcinoma; Patient Selection; Patients; Population; Primary Neoplasm; Public Health; Radiation therapy; Rate; Recurrence; Renal Cell Carcinoma; Reporting; Research; Research Personnel; Residual state; Risk; Site; Survival Rate; System; Thermal Ablation Therapy; Tissues; Toxic effect; Treatment outcome; Tumor Antigens; Vaccines; Work; base; cancer therapy; cell motility; chemotherapy; cytokine; day; design; efficacy evaluation; improved; in vivo; inclusion criteria; lymph nodes; macrophage; malignant breast neoplasm; melanoma; migration; model development; mouse model; neoplastic cell; novel; novel strategies; osteosarcoma; response; subcutaneous; tumor; tumor growth

DESCRIPTION (provided by applicant): High intensity focused ultrasound (HIFU) has gained significant ground as a promising, non-ionizing, non-invasive method of the treatment for a variety of cancers. Although clinical trials have demonstrated its unique advantages, a broad scope of HIFU application in cancer therapy is still limited by the stringent inclusion criteria in patient selection. Furthermore, HIFU as it is currently employed cannot treat distant metastasis, and it may lead to local recurrence in cases of incomplete tissue necrosis. In light of these shortcomings, it is important to explore novel implementation strategies of HIFU within a larger framework of multi-treatment modalities for cancer therapy. Such combinational strategies may increase the effectiveness and application spectrum of HIFU as well as the overall outcome of existing cancer treatment modalities. Recent investigations have demonstrated encouraging results of a HIFU-elicited anti-tumor immune response. HIFU may induce changes in the tumor microenvironment that are conducive for stimulating a tumor specific immune response which can be exploited through a synergistic combination with other established cancer treatment modalities for improved efficacy. In preliminary studies, we have shown in vivo that mechanical lysis of tumor cells with HIFU yields an increase in dendritic cell (DC) infiltration to the tumor with subsequent migration to the draining lymph nodes, a critical step in eliciting an anti-tumor immune response. Also, in a B16 murine melanoma model, we have observed a decrease in metastasis rates when subcutaneous tumors were treated with HIFU two days before surgical resection. In contrast, when surgery was performed immediately following HIFU treatment, thus eliminating the possibility of DC infiltration and maturation at the damaged tumor site, there was no observed significant difference in metastasis rates. While current HIFU clinical trials are mainly focused on producing localized thermal ablation of the primary tumor, there is conceptually an even greater potential for utilizing HIFU as an adjuvant therapy within the large multimodality framework of cancer therapy. For example, HIFU may be implemented as an outpatient pretreatment to suppress the primary tumor growth while stimulating concomitantly an anti-tumor immune response before surgery, radiotherapy, and/or chemotherapy for the large population of cancer patients who may not be eligible for HIFU monotherapy. Furthermore, combinations of HIFU with other immunotherapeutic strategies such as dendritic cell or cytokine-based vaccines may yield improved responses through synergistic interactions. PUBLIC HEALTH RELEVANCE: The objective of this exploratory R21 proposal is therefore two-fold: 1) To optimize HIFU treatment parameters to maximize the elicited anti-tumor immune response in a B16 melanoma mouse tumor model, and 2) to investigate the synergistic combination of HIFU with dendritic cell and GM-CSF injections in suppressing distant metastasis in the melanoma mouse model post-surgical resection of the primary tumor.

描述（由申请人提供）：高强度聚焦超声（HIFU）作为一种有前途的、非电离的、非侵入性的治疗多种癌症的方法已经取得了显着的进展。尽管临床试验已经证明了其独特的优势，但HIFU在癌症治疗中的广泛应用仍然受到严格的患者选择标准的限制。此外，目前使用的HIFU不能治疗远处转移，在组织不完全坏死的情况下可能导致局部复发。鉴于这些缺点，在癌症治疗的多治疗模式的更大框架内探索 HIFU 的新实施策略非常重要。这种组合策略可能会增加 HIFU 的有效性和应用范围以及现有癌症治疗方式的总体结果。最近的研究表明 HIFU 引发的抗肿瘤免疫反应取得了令人鼓舞的结果。 HIFU 可能会引起肿瘤微环境的变化，从而有利于刺激肿瘤特异性免疫反应，这种免疫反应可以通过与其他已建立的癌症治疗方式的协同组合来利用，以提高疗效。在初步研究中，我们在体内证明，用 HIFU 机械裂解肿瘤细胞会增加树突状细胞 (DC) 向肿瘤的浸润，并随后迁移到引流淋巴结，这是引发抗肿瘤免疫反应的关键步骤。此外，在 B16 小鼠黑色素瘤模型中，我们观察到在手术切除前两天用 HIFU 治疗皮下肿瘤时，转移率降低。相比之下，当HIFU治疗后立即进行手术，从而消除了受损肿瘤部位DC浸润和成熟的可能性时，没有观察到转移率的显着差异。虽然目前的 HIFU 临床试验主要集中于对原发肿瘤进行局部热消融，但从概念上讲，在癌症治疗的大型多模式框架内利用 HIFU 作为辅助治疗具有更大的潜力。例如，HIFU可以作为门诊预处理来抑制原发性肿瘤生长，同时在手术、放疗和/或化疗之前对可能不适合HIFU单一疗法的大量癌症患者刺激抗肿瘤免疫反应。此外，HIFU 与其他免疫治疗策略（例如树突状细胞或细胞因子疫苗）的组合可能通过协同相互作用产生改善的反应。公共健康相关性：因此，这一探索性 R21 提案的目标有两个：1) 优化 HIFU 治疗参数，以最大限度地提高 B16 黑色素瘤小鼠肿瘤模型中引发的抗肿瘤免疫反应，2) 研究 HIFU 与树突状细胞和 GM-CSF 注射的协同组合在抑制黑色素瘤小鼠模型术后远处转移中的作用 切除原发肿瘤。