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The abscopal effect of nanosecond electric pulse tumor ablation and its enhancement for metastatic breast cancer

纳秒电脉冲肿瘤消融及其强化治疗转移性乳腺癌的远隔效应

基本信息

批准号：
9756343
负责人：
Siqi Guo
金额：
$ 16.35万
依托单位：
OLD DOMINION UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-06 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756343
关键词：
Abscopal effect Address Animal Model Animals Antibodies Breast Cancer Model Breast Cancer Patient Calcium Cell Death Cells Cessation of life Cytotoxic T-Lymphocytes Data Defect Dendritic Cells Distant Electrical Engineering Electroporation Endoplasmic Reticulum Environment Event Exhibits Immune Immune response Immunomodulators Immunotherapeutic agent Infiltration Interleukin-15 Ionizing radiation Length Lesion Literature Malignant Neoplasms Membrane Membrane Potentials Memory Metastatic breast cancer Modeling Mole the mammal Mus Myeloid-derived suppressor cells Natural Immunity Natural Killer Cells Neoplasm Metastasis Organ Organelles Pharmaceutical Preparations Physiologic pulse Plasma Plasmids Primary carcinoma of the liver cells Publishing Radiation therapy Rattus Regulatory T-Lymphocyte Reporting Research Role Suggestion T memory cell T-Lymphocyte Technology Testing Time Translating Tumor Immunity Tumor-associated macrophages Universities Vaccines Vesicle Work adaptive immunity anti-PD-1 base cancer cell cell type curative treatments cytotoxic electric field falls immunogenic improved minimally invasive mitochondrial membrane nanosecond neoplastic cell novel preclinical study prevent protective effect tumor tumor ablation tumor microenvironment

项目摘要

Project Summary: Metastatic breast cancer (MBC) is responsible for 90% of patient breast cancer deaths with no curative therapies currently available. Our discovery, as shown in our preliminary data, of an abscopal effect following nanosecond electric pulse (nsEP) tumor treatment reveals a promising novel immunotherapeutic approach to control or treat MBC in conjunction with the local nsEP tumor ablation. Currently nsEPs, an electrical engineering technology, have been developed and utilized to treat cancer in animal models. Preclinical studies on nsEP applications have focused mainly on local tumor ablation, however, a concurrent vaccine-like protective effect has been reported in the literature in an orthotopic hepatocellular carcinoma model following nsEP treatment. Recently, we've discovered an abscopal effect resulting from local tumor ablation by nsEPs in an orthotopic murine breast cancer model. Our preliminary data showed nsEP tumor ablation not only ablated the local tumor but also prevented spontaneous organ metastases and rejected existing distant tumors. Furthermore, we demonstrated remarkable changes of immune profiles of tumor animals treated with nsEPs where extremely suppressive local and systemic immune environments in tumor-bearing animals were diminished after successful nsEP treatment. Meanwhile, central and effector memory T cells were established, exhibiting cytotoxic functions. Our data also suggest the efficacy of nsEPs for tumor regression could be further improved in combination with other immunomodulators. Based on the above preliminary findings, we hypothesize that the abscopal effect following nsEP tumor ablation is due to antitumor immunity induced by nsEP treatment with the potential to be enhanced with other immunomodulators. Two specific aims will be addressed to test our hypothesis. In Aim 1, we will evaluate: (a) the influence of nsEP parameters on the abscopal effect, (b) the strength of the abscopal effect, and (c) the enhancement of the abscopal effect with immunomodulators targeting major immune defects of the tumor. In Aim 2, we will explore the immune mechanisms of the abscopal effect resulting from nsEP tumor ablation. We will characterize the change of tumor microenvironment, local and systemic immune responses following nsEP tumor ablation, and determine the role of innate or adaptive immunity for the abscopal effect. The nsEP technology is a drug-free, ionizing radiation-free, and non-thermal therapy that can treat cancer in a fast and minimally invasive manner. Successful results from this study would translate to a breakthrough tumor regression or potentially curative therapy for metastatic breast cancer.

项目总结：转移性乳腺癌(MBC)是导致90%没有治愈的乳腺癌患者死亡的原因。目前可用的治疗方法。我们的发现，如我们的初步数据所示，以下是一种非范围效应纳秒电脉冲(NsEP)治疗肿瘤揭示了一种有前途的新的免疫治疗方法在局部nsEP肿瘤消融的同时控制或治疗MBC。目前，nsEPs是一种电子设备工程技术已被开发并用于治疗动物模型中的癌症。临床前研究关于nsEP的应用主要集中在局部肿瘤消融上，然而，一种类似疫苗的并发应用文献报道了在以下原位肝细胞癌模型中的保护作用 NsEP治疗。最近，我们发现了nsEP局部消融肿瘤引起的一种非局域效应。一种原位小鼠乳腺癌模型。我们的初步数据显示nsEP肿瘤消融术不仅消融了局部肿瘤还可防止自发性器官转移和排斥现有的远处肿瘤。此外，我们还证实了nsEPs对肿瘤动物免疫功能的显著影响。荷瘤动物体内极具抑制性的局部和全身免疫环境在成功的nsEP治疗后减弱。同时建立了中枢和效应性记忆T细胞，表现出细胞毒性作用的。我们的数据还表明，nsEPs在肿瘤消退方面的疗效可能会进一步与其他免疫调节剂联合使用时效果更佳。基于上述初步发现，我们假设nsEP肿瘤后的非局部性效应消融是由于nsEP治疗诱导的抗肿瘤免疫，有可能得到增强与其他免疫调节剂一起使用。两个具体的目标将被用来检验我们的假设。在目标1中，我们将评估：(A)nsEP参数对离域效应的影响，(B)离域效应的强度，和(C)通过针对主要免疫缺陷的免疫调节剂增强异常效应肿瘤。在目标2中，我们将探索nsEP肿瘤引起的异常效应的免疫机制。消融。我们将描述肿瘤微环境、局部和全身免疫反应的变化。 NsEP肿瘤消融后，确定先天免疫或获得性免疫的异位效应。 NsEP技术是一种无药物、无电离辐射和非热疗的疗法，可以在快速和微创的方式。这项研究的成功结果将转化为突破性的肿瘤转移性乳腺癌的消退或潜在根治疗法。