Department of Chemical Engineering, University of Massachusetts, Amherst, MA.
Int J Cancer. 2014 Aug 1;135(3):647-57. doi: 10.1002/ijc.28700. Epub 2014 Jan 10.
Engineered Salmonella have the potential to treat cancers that are not responsive to standard molecular therapies. This potential has not been realized because colonization in human tumors is insufficient and variable as shown in preliminary phase I trials. Recent studies have shown that Salmonella colonization is associated with an inflammatory response mediated by tumor necrosis factor (TNF). An injectable agent, molecular lipid A, could be used to control bacterial accumulation because it induces TNF production and is rapidly cleared. We hypothesized that concurrently administrating lipid A with attenuated Salmonella would increase intratumoral accumulation, improve the robustness of tumor-targeting and be nontoxic. To test this hypothesis, Salmonella and lipid A were injected into mice with 4T1 mammary tumors. Colonization was quantified after 48 hr using anti-Salmonella immunofluorescence. A 2 μg/mouse dose of lipid A increased the area of colonized tissue fourfold, reduced variance 50% and ensured colonization in all mice. Comparatively, Salmonella failed to colonize some control mice, similar to human trials. No toxicity was observed in any treated mice. The fraction of tumor tissue with more than 25% bacterial coverage was eight times greater for treated mice compared to controls. Lipid A treatment also reduced the maximum average distance of tissue to Salmonella colonies from 1348 to 260 μm. A mathematical model of bacterial drug production predicted that 2 μg lipid A would increase tumor cell death by 82%. These results suggest that lipid A could solve the clinical challenges of Salmonella therapy and enable safe and robust treatment of cancer with bacteria.
经工程改造的沙门氏菌有可能治疗对标准分子疗法没有反应的癌症。这种潜力尚未实现，因为初步 I 期试验表明，沙门氏菌在人类肿瘤中的定植不足且具有变异性。最近的研究表明，沙门氏菌定植与肿瘤坏死因子 (TNF) 介导的炎症反应有关。一种可注射的试剂，即分子脂质 A，可以用于控制细菌积累，因为它可以诱导 TNF 的产生并迅速被清除。我们假设同时给予脂质 A 和减毒沙门氏菌会增加肿瘤内积累，提高肿瘤靶向的稳健性且无毒性。为了验证这一假设，我们将沙门氏菌和脂质 A 注射到患有 4T1 乳腺肿瘤的小鼠体内。在 48 小时后使用抗沙门氏菌免疫荧光术来量化定植。2 μg/只的脂质 A 剂量将定植组织的面积增加了四倍，将变异性降低了 50%，并确保所有小鼠都定植。相比之下，一些对照小鼠中，沙门氏菌未能定植，这与人类试验相似。任何治疗小鼠均未观察到毒性。与对照组相比，治疗组中具有超过 25%细菌覆盖的肿瘤组织比例增加了 8 倍。脂质 A 治疗还将组织中沙门氏菌菌落的最大平均距离从 1348 减少到 260 μm。细菌药物生产的数学模型预测，2 μg 脂质 A 将使肿瘤细胞死亡增加 82%。这些结果表明，脂质 A 可以解决沙门氏菌治疗的临床挑战，并能够安全而稳健地用细菌治疗癌症。
