Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN, USA.
Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
J Drug Target. 2021 Apr;29(4):430-438. doi: 10.1080/1061186X.2020.1850739. Epub 2020 Dec 21.
The ultimate goal of bacterial based cancer therapy is to achieve non-toxic penetration and colonisation of the tumour microenvironment. To overcome this efficacy-limiting toxicity of anticancer immunotherapy, we have tested a therapy comprised of systemic delivery of a vascular disrupting agent to induce intratumoral necrotic space, cannabidiol to temporarily inhibit angiogenesis and acute inflammation, and a strain of Typhimurium that was engineered for non-toxic colonisation and expression of immunomodulators within the tumour microenvironment. This combination treatment strategy was administered to transgenic mice burdened with autochthonous mammary gland tumours and demonstrated a statistically significant 64% slower tumour growth and a 25% increase in mean survival time compared to control animals without treatment. These experiments were accomplished with minimal toxicity as measured by less than 7% weight loss and a return to normal weight gain within three days following intravenous administration of the bacteria. Thus, non-toxic, robust colonisation of the microenvironment was achieved to produce a significant antitumor effect.
基于细菌的癌症治疗的最终目标是实现对肿瘤微环境的无毒穿透和定植。为了克服抗癌免疫疗法的这种疗效限制毒性，我们已经测试了一种治疗方法，包括全身递送血管破坏剂以诱导肿瘤内坏死空间、大麻二酚暂时抑制血管生成和急性炎症，以及一株经过工程改造的 Typhimurium ，可在肿瘤微环境中进行无毒定植和免疫调节剂的表达。该联合治疗策略用于携带同源乳腺肿瘤的转基因小鼠，并与未接受治疗的对照动物相比，肿瘤生长速度统计学上显著减慢了 64%，平均存活时间延长了 25%。这些实验的完成毒性极小，通过静脉内给予细菌后不到 7%的体重减轻和三天内体重恢复正常来衡量。因此，实现了无毒、稳健的微环境定植，从而产生了显著的抗肿瘤效果。
