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

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得到了广泛的重视。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患者选择的严格纳入标准的限制。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，它可能会导致局部复发。鉴于这些缺点，重要的是在癌症治疗的多种治疗模式的更大框架内探索HIFU的新实施战略。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诱导的抗肿瘤免疫反应取得了令人鼓舞的结果。HIFU可引起肿瘤微环境的变化，有利于刺激肿瘤特异性免疫反应，可通过与其他已建立的癌症治疗方法的协同作用来提高疗效。在初步研究中，我们已经在体内表明，用HIFU机械溶解肿瘤细胞会增加树突状细胞(DC)对肿瘤的渗透，随后迁移到引流的淋巴结，这是激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接受HIFU治疗的皮下肿瘤转移率降低。相反，当在HIFU治疗后立即进行手术，从而消除了受损肿瘤部位DC渗透和成熟的可能性，转移率没有观察到显著差异。虽然目前的HIFU临床试验主要集中在对原发肿瘤进行局部热消融，但在癌症治疗的大型多模式框架内，概念上仍有更大的潜力将HIFU用作辅助治疗。例如，HIFU可以作为门诊预处理来实施，以抑制原发肿瘤的生长，同时在手术、放射治疗和/或化疗之前为可能没有资格接受HIFU单一治疗的大量癌症患者同时刺激抗肿瘤免疫反应。此外，HIFU与树突状细胞或细胞因子疫苗等其他免疫治疗策略的结合可能通过协同作用产生更好的反应。公共卫生相关性：因此，这项探索性R21提案的目的有两个：1)优化HIFU治疗参数，以最大限度地激发B16黑色素瘤小鼠肿瘤模型中诱导的抗肿瘤免疫反应；2)研究HIFU与树突状细胞和GM-CSF注射在抑制黑色素瘤小鼠原发肿瘤手术后远处转移中的协同作用。

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.