Abstract
Introduction: Pancreatic ductal adenocarcinoma (pancreatic cancer), is the 4th leading cause of cancer deaths. This “silent killer” is characterized by metastases occurring often before the primary tumor can be detected, resulting in a five-year survival rate of only 4%, underscoring the need for new alternative therapies. Listeria monocytogenes-based cancer therapy could be such an alternative. Our laboratory discovered that attenuated Listeria exhibits novel pathways that are particularly useful against metastatic cancer. We found that Listeria infects metastases and primary tumors, and kills tumor cells through high levels of reactive oxygen species (ROS), and that myeloid-derived suppressor cells (MDSC) deliver Listeria selectively to the tumor site(s) through chemo/cytokines produced by the tumor cells, and by protecting them, after infection, from immune clearance through their immune suppressive character. Based on these results we now use Listeria as a platform for the delivery of anticancer agents to the tumor microenvironment (TME). One novel application is the delivery of radioisotopes, which emit cytocidal radiation such as beta-particles coupled to Listeria, selectively into the tumor cells. This leads to the synergistic destruction of tumor cells by ionizing radiation, through beta-particles and through ROS generation by Listeria. We were the first to demonstrate that in a highly aggressive model of pancreatic cancer (Panc-02), therapeutic treatment with Listeria reduced the number of metastases by 50%, and when coupled to radioisotope 188-Rhenium (188Re) by 90%. This correlated with a selective accumulation of radioactivity in the metastases without significant side effects.
Experimental procedures: Most recently, we explored a completely new method to RL generation using 32Phosphorus (32P), by incorporating 32P into the cell wall of Listeria (Listeria-32P) during culturing of Listeria. Panc-02 mice received 12 doses of Listeria-32P over a period of 28 days.
Results: Treatment with Listeria-32P completely eliminated the metastatic cancer in 90% of the mice (visible by eye), while survival studies demonstrated that 43% of the mice were still alive and free of cancer (confirmed by histological examination) 3 months after the last treatment. Untreated mice die within 30-35 days. Most importantly, the incorporation of 32P delivered through Listeria into normal tissues including bone marrow (BM) was hardly detectable, in contrast to 32P alone, which strongly incorporated into the BM.
In conclusion: We have developed a novel non-toxic strategy that is highly effective against pancreatic cancer in a preclinical model Panc-02, with a goal to treat patients with pancreatic cancer in the near future. Currently, we are testing Listeria-32P in KPC transgenic mice (conditionally express endogenous Kras-G12D and p53-R172H mutant alleles), which is a humanized model of spontaneous pancreatic cancer.
Citation Format: Dinesh Chandra, Ziqiang Yuan, Steven K. Libutti, Ekaterina Dadachova, Claudia Gravekamp. Listeria-32P, a new approach to treat pancreatic cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A184.
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