Department of Microbiology and Immunology and Department of Radiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8668-73. doi: 10.1073/pnas.1211287110. Epub 2013 Apr 22.
No significant improvement in therapy of pancreatic cancer has been reported over the last 25 y, underscoring the urgent need for new alternative therapies. Here, we coupled a radioisotope, (188)Rhenium, to an attenuated (at) live Listeria monocytogenes (Listeria(at)) using Listeria-binding antibodies, thus creating a unique radioactive Listeria(at) (RL). We then demonstrated in a highly metastatic pancreatic mouse tumor model (Panc-02) that RL delivered radioactivity to the metastases and less abundantly to primary tumors in vivo, without harming normal cells. This result was possible because Listeria(at) was efficiently cleared by the immune system in normal tissues but not in the heavily immune-suppressed microenvironment of metastases and primary tumor. Multiple treatments with low doses of the RL resulted in a dramatic decrease in the number of metastases (~90%) compared with control groups in the Panc-02 model. This is the first report of using live attenuated bacteria delivering a highly radioactive payload to the metastases, resulting in killing tumor cells in vivo without harming normal cells. The nontoxic RL treatment is attractive for clinical development as a therapy to prevent pancreatic cancer recurrence and metastases.
在过去的 25 年中，胰腺癌的治疗并没有显著改善，这凸显了迫切需要新的替代疗法。在这里，我们使用李斯特菌结合抗体将放射性同位素（188）铼与减毒（at）活李斯特菌（李斯特菌（at））结合，从而创造了一种独特的放射性李斯特菌（at）（RL）。然后，我们在一种高度转移性胰腺小鼠肿瘤模型（Panc-02）中证明，RL 在体内将放射性物质输送到转移灶，而在原发肿瘤中输送的放射性物质较少，但不会伤害正常细胞。之所以能够实现这一结果，是因为李斯特菌（at）在正常组织中被免疫系统有效地清除，但在转移灶和原发肿瘤中免疫抑制严重的微环境中却无法清除。与对照组相比，用低剂量 RL 多次治疗可使 Panc-02 模型中的转移灶数量显著减少（约 90%）。这是首次报道使用活减毒细菌将高放射性有效载荷输送到转移灶，从而在不伤害正常细胞的情况下杀死体内的肿瘤细胞。这种非毒性的 RL 治疗具有吸引力，可作为预防胰腺癌复发和转移的治疗方法进行临床开发。
