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

项目摘要： 转移性乳腺癌（MBC）是导致90%的乳腺癌患者死亡的原因， 目前可用的疗法。我们的发现，如我们的初步数据所示， 纳秒电脉冲（nsEP）肿瘤治疗揭示了一种有前途的新的免疫方法， 结合局部nsEP肿瘤消融控制或治疗MBC。目前，nsEPs是一种电气 工程技术，已经被开发并用于在动物模型中治疗癌症。临床前研究 关于nsEP应用的研究主要集中在局部肿瘤消融，然而， 文献中报道了在原位肝细胞癌模型中的保护作用， nsEP治疗。最近，我们已经发现了由nsEP局部肿瘤消融引起的远位效应， 原位鼠乳腺癌模型。我们的初步数据显示，nsEP肿瘤消融不仅消融了 局部肿瘤，但也防止自发性器官转移和排斥现有的远处肿瘤。 此外，我们证明了用nsEP治疗的肿瘤动物的免疫谱的显著变化 在荷瘤动物中， 在成功的nsEP治疗后减少。同时，建立了中枢和效应记忆T细胞， 表现出细胞毒性功能。我们的数据还表明，nsEP对肿瘤消退的疗效可能进一步提高。 与其他免疫调节剂组合改善。 基于上述初步发现，我们假设nsEP肿瘤后的远位效应 消融是由于nsEP治疗诱导的抗肿瘤免疫，具有增强的潜力 与其他免疫调节剂。为了检验我们的假设，将提出两个具体目标。在目标1中，我们 评价：（a）nsEP参数对远端效应的影响，（B）远端效应的强度， 和（c）用免疫调节剂增强远位效应，所述免疫调节剂靶向所述组织的主要免疫缺陷， 肿瘤目的二：探讨nsEP肿瘤引起远位效应的免疫机制 消融术我们将描述肿瘤微环境的变化，局部和全身免疫反应 在nsEP肿瘤消融后，并确定先天性或适应性免疫对远位效应的作用。 nsEP技术是一种无药物，无电离辐射和非热疗法，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治愈性治疗。

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.