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、非侵入性的治疗各种癌症的方法，已经获得了显著的基础。尽管临床试验已经证明了其独特的优势，但由于严格的入选标准，HIFU在肿瘤治疗中的广泛应用仍然受到限制。此外，目前采用的HIFU不能治疗远处转移，并且在不完全组织坏死的情况下可能导致局部复发。鉴于这些缺点，重要的是要探索新的实施策略的HIFU在更大的框架内的多种治疗模式的癌症治疗。这种组合策略可以增加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。最近的研究已经证明了HIFU引起的抗肿瘤免疫应答的令人鼓舞的结果。HIFU可以诱导肿瘤微环境的变化，这有助于刺激肿瘤特异性免疫应答，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这种免疫应答以提高疗效。在初步研究中，我们已经在体内表明，用HIFU机械裂解肿瘤细胞会增加树突状细胞（DC）浸润肿瘤，随后迁移到引流淋巴结，这是引发抗肿瘤免疫应答的关键步骤。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DC浸润和成熟的可能性在受损的肿瘤部位，没有观察到转移率的显着差异。虽然目前的HIFU临床试验主要集中在原发性肿瘤的局部热消融，但在概念上，在癌症治疗的大型多模态框架内，利用HIFU作为辅助治疗具有更大的潜力。例如，对于可能不适合HIFU单一疗法的大量癌症患者，HIFU可以作为门诊预处理来实施，以在手术、放疗和/或化疗之前抑制原发性肿瘤生长，同时伴随地刺激抗肿瘤免疫应答。此外，高强度聚焦超声与其他免疫策略如树突状细胞或基于精氨酸的疫苗的组合可以通过协同相互作用产生改善的反应。公共卫生相关性：因此，该探索性R21提案的目的是双重的：1）优化HIFU治疗参数以使B16黑色素瘤小鼠肿瘤模型中引发的抗肿瘤免疫应答最大化，以及2）研究HIFU与树突状细胞和GM-CSF注射的协同组合在原发性肿瘤手术切除后抑制黑色素瘤小鼠模型中的远处转移。

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.