Abstract

Much of the bacterial anticancer therapy being developed relies on the ability of bacteria to specifically colonise tumours. Initial attempts to translate promising Salmonella enterica Typhimurium (S. Typhimurium) preclinical results to the clinical setting failed, primarily due to lack of tumour colonisation and the significant toxicities from systemically administered Gram-negative bacteria. To address the difference in results between preclinical experiments performed in mice with transplant tumours and clinical trials in human volunteers with autochthonous tumours, a genetically engineered mouse model of breast cancer (BALB-neuT) was utilised to develop a strain of virulence-attenuated S. Typhimurium capable of robust colonisation of autochthonous tumours. Several genes that code for bacterial surface molecules, responsible for signalling a toxic immune response against the bacteria, were mutated. The resulting S. Typhimurium strain, BCT2, allowed non-toxic intravenous administration of 3 × 10⁶ colony forming units of bacteria in tumour-burdened mice when combined with a vascular disruption agent to induce intratumoral necrotic space and facilitate bacterial colonisation.

摘要

许多正在开发的细菌抗癌疗法依赖于细菌特异性定殖肿瘤的能力。将有希望的肠道沙门氏菌 ( S. Typhimurium) 临床前结果转化为临床环境的初步尝试失败了，主要是由于缺乏肿瘤定植和全身施用革兰氏阴性菌的显着毒性。为了解决在移植肿瘤小鼠中进行的临床前实验与在患有本土肿瘤的人类志愿者中进行的临床试验之间结果的差异，利用乳腺癌基因工程小鼠模型 (BALB-neuT) 来开发毒力减弱的S. 鼠伤寒杆菌能够在本土肿瘤中进行稳健的定植。几个编码细菌表面分子的基因发生了突变，这些基因负责发出针对细菌的有毒免疫反应的信号。将所得S.鼠伤寒沙门氏菌菌株，BCT2，允许3×10的无毒静脉内施用⁶当与血管破坏剂组合以诱导瘤内坏死的空间，便于细菌定植菌落形成在荷瘤小鼠中的细菌的单元。