Optimization of Non-Ablative Focused Ultrasound Therapy for Tumor Immunity

 描述（由申请人提供）：本项目的总体目标是开发一种安全、无创的非消融性聚焦超声治疗（NAFU），通过增加肿瘤免疫原性，用于治疗原发性肿瘤和预防转移。NAFU治疗可用作当前疗法的辅助疗法，例如化学疗法、免疫疗法、手术、放射疗法和HIFU。该提案将确立NAFU在产生系统性抗肿瘤免疫中的作用，并定义诱导ER应激和增强肿瘤免疫调节标志物（如热休克蛋白70、钙网蛋白、ATP和HMGB1）的特定方案。NAFU将与两种不同的新型免疫疗法相结合：基于树突状细胞的疫苗和基于李斯特菌的前列腺癌疫苗。初步数据表明，NAFU处理增加细胞表面免疫调节，当与树突状细胞离体培养时，其将导致增强的自体疫苗。此外，初步研究表明，NAFU治疗基于李斯特菌的前列腺癌减毒活疫苗增强了细菌的吞噬作用，导致更强大的免疫应答和肿瘤负荷的控制。这些项目将共同巩固非消融聚焦超声作为一种有效的癌症治疗选择，这将诱导全身抗肿瘤免疫，治疗原发性肿瘤，并减少转移。

 DESCRIPTION (provided by applicant): The overall goal of this project is to develop a safe, non-invasive non-ablative focused ultrasound therapy (NAFU) which can be used for the treatment of primary carcinoma and prevention of metastases by increasing tumor immunogenicity. NAFU treatment be used as an adjuvant therapy with current therapies, such as chemotherapy, immunotherapy, surgery, radiotherapy, and HIFU. This proposal will establish the role of NAFU in generating systemic anti-tumor immunity and define specific protocols for inducing ER stress and augmenting tumor immunomodulatory markers, such as heat shock protein 70, calreticulin, ATP and HMGB1. NAFU will be combined with two different novel immunotherapies: a dendritic cell-based vaccine and a Listeria-based prostate cancer vaccine. Preliminary data indicates that NAFU-treatment increases cell surface immunomodulation, which when cultured with dendritic cells ex vivo will result in an enhanced autologous vaccine. Additionally, preliminary studies demonstrate that NAFU-treatment of a live, attenuated Listeria-based vaccine for prostate cancer enhances phagocytosis of the bacteria, resulting in a more robust immune response and control of tumor burden. Together these projects will solidify non-ablative focused ultrasound as an effective cancer treatment option which will induce systemic anti-tumor immunity, treat primary tumors, and reduce metastases.