PDF(Pubmed)
Abstract：
Background and rationale: Attenuated Salmonella typhimurium VNP20009 has been used to treat tumor-bearing mice and entered phase I clinical trials. However, its mild anticancer effect in clinical trials may be related to insufficient bacterial colonization and notable adverse effects with increasing dosages. Guanosine 5\'-diphosphate-3\'-diphosphate (ppGpp) synthesis-deficient Salmonella is an attenuated strain with good biosafety and anticancer efficacy that has been widely investigated in various solid cancers in preclinical studies. Integration of the advantages of these two strains may provide a new solution for oncolytic bacterial therapy. Methods: We incorporated the features of ΔppGpp into VNP20009 and obtained the HCS1 strain by deleting relA and spoT, and then assessed its cytotoxicity in vitro and antitumor activities in vivo. Results: In vitro experiments revealed that the invasiveness and cytotoxicity of HCS1 to cancer cells were significantly lower than those of the VNP20009. Additionally, tumor-bearing mice showed robust cancer suppression when treated with different doses of HCS1 intravenously, and the survival time and cured mice were dramatically increased. Furthermore, HCS1 can increase the levels of pro-inflammatory cytokines in tumor tissues and relieve the immunosuppression in the tumor microenvironments. It can also recruit abundant immune cells into tumor tissues, thereby increasing immune activation responses. Conclusion: The newly engineered Salmonella HCS1 strain manifests high prospects for cancer therapeutics and is a promising option for future clinical cancer immunotherapy.
摘要：
背景和原理：减毒鼠伤寒沙门氏菌VNP20009已用于治疗荷瘤小鼠并进入I期临床试验。然而,在临床试验中，其温和的抗癌作用可能与细菌定植不足以及随着剂量增加而产生的明显不良反应有关。鸟苷5'-二磷酸-3'-二磷酸（ppGpp）合成缺陷型沙门氏菌是一种具有良好生物安全性和抗癌功效的减毒菌株，已在临床前研究中广泛用于各种实体癌中。这两种菌株优势的整合可能为溶瘤细菌治疗提供新的解决方案。方法：我们将ΔppGpp的特征整合到VNP20009中，并通过删除relA和spot获得HCS1菌株，然后评估其体外细胞毒性和体内抗肿瘤活性。结果：体外实验表明，HCS1对癌细胞的侵袭力和细胞毒性明显低于VNP20009。此外,用不同剂量的HCS1静脉注射治疗时，荷瘤小鼠显示出强大的癌症抑制作用，存活时间和治愈的小鼠显著增加。此外，HCS1可以提高肿瘤组织中促炎细胞因子的水平，缓解肿瘤微环境中的免疫抑制。它还可以招募丰富的免疫细胞进入肿瘤组织，从而增加免疫激活反应。结论：新设计的沙门氏菌HCS1菌株具有很高的癌症治疗前景，是未来临床癌症免疫治疗的有希望的选择。
