Cancer therapy with a combination of oncolytic bacteria and virus to enhance targeted cell killing and anti-tumor immune responses

项目摘要/摘要 癌症是美国和全世界的主要死亡原因之一。适当地激活 免疫系统和肿瘤细胞的有效靶向是成功克服的主要障碍 癌症免疫疗法。最近，基于微生物的治疗被广泛研究以填补危重的未满足的疾病 癌症患者的需求，目前的治疗选择已经用尽。我们已经开发出 基因工程沙门氏菌(GMS)可以主动寻找癌细胞，诱导肿瘤消退， 延长多种小鼠模型的存活时间，抑制肿瘤转移。他们还可以根除 治疗后从宿主身上脱身。有趣的是，沙门氏菌还处理多种自然杀手(NK) 细胞刺激物。另一方面，溶瘤病毒是一种新的癌症免疫疗法，已被 批准在临床上使用。溶瘤性粘液瘤病毒(MYXV)已在多种临床前癌症中进行检测 模型，并已证明免疫刺激特性用于癌症治疗。MYXV能够带来 CD45+白细胞进入肿瘤床。此外，这些大型DNA病毒可以被武装起来表达额外的 免疫激活分子。在这项研究中，我们建议探索一种新的癌症治疗方法， 结合了细菌的靶向杀灭癌细胞的能力和两者的免疫刺激能力 细菌和病毒。除了直接杀死癌细胞外，改良的GMS还将刺激NK细胞和 MYXV将招募其他肿瘤浸润性白细胞来激活抗肿瘤免疫反应。此外, 我们将探索表达细胞因子和趋化因子的转基因武装MYXV来招募 更具特异性的肿瘤浸润性白细胞。我们的努力的成功将使微生物在现场变得合适 免疫系统的吸引物和激活剂有效的癌症治疗的成功和适用 横跨多种肿瘤类型。

Project Summary/Abstract Cancer is one of the leading causes of death in the United States and worldwide. Appropriate activation of the immune system and effective targeting of tumor cells are the primary hurdles to be overcome for successful cancer immunotherapy. Microbes-based therapy was extensively studied recently to fill the critical unmet needs of cancer patients, where the current treatment options have been exhausted. We have developed genetically engineered Salmonella (GMS), which can actively search for cancer cells, induce tumor regression, prolong survival time, and inhibit cancer metastasis in multiple mouse models. They can also eradicate themselves from the host after treatment. Interestingly, Salmonella also processes multiple natural killer (NK) cell stimulators. On the other hand, oncolytic viruses are new cancer immunotherapeutics and have been approved to use in the clinic. Oncolytic Myxoma virus (MYXV) has been tested in multiple preclinical cancer models and has demonstrated immune stimulating properties for cancer treatment. MYXV was able to bring CD45+ leukocytes to the tumor bed. In addition, these large DNA viruses can be armed to express additional immune activating molecules. In this study, we propose to explore a novel cancer treatment approach that combines the targeted cancer cell killing ability of bacteria and immune stimulating abilities of both oncolytic bacteria and viruses. Apart from the direct killing of cancer cells, improved GMS will stimulate NK cells and MYXV will recruit other tumor-infiltrating leukocytes to activate the anti-tumor immune responses. In addition, we will explore the transgene expressing armed MYXVs that will express cytokines and chemokines to recruit more specific tumor-infiltrating leukocytes. The success of our efforts would turn microbes to appropriate onsite attractors and activators of the immune system for effective cancer therapy to be successful and applicable across a wide range of tumor types.