32-Phosphorus selectively delivered by listeria to pancreatic cancer demonstrates a strong therapeutic effect

// Dinesh Chandra 1 , Benson Chellakkan Selvanesan 1 , Ziqiang Yuan 2 , Steven K Libutti 2 , Wade Koba 3 , Amanda Beck 4 , Kun Zhu 1 , Arturo Casadevall 5 , Ekaterina Dadachova 6 , Claudia Gravekamp 1 1 Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461, USA 2 Montefiore Medical Center, Medical Arts Pavilion, MMC-MAP, Bronx, NY 10467, USA 3 Albert Einstein College of Medicine, Department of Radiology, MRRC, Bronx, NY 10461, USA 4 Albert Einstein College of Medicine, Department of Pathology, Michael F. Price Center, Bronx, NY 10461, USA 5 Johns Hopkins Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Baltimore, MD 21205, USA 6 Albert Einstein College of Medicine, Department of Radiology/Department of Microbiology and Immunology, Bronx, NY 10461, USA Correspondence to: Claudia Gravekamp, email: claudia.gravekamp@einstein.yu.edu Keywords: listeria monocytogenes, 32 P, pancreatic cancer, KPC, Panc-02, delivery platform Received: August 24, 2016      Accepted: January 24, 2017      Published: February 06, 2017 ABSTRACT Our laboratory has developed a novel delivery platform using an attenuated non-toxic and non-pathogenic bacterium Listeria monocytogenes that infects tumor cells and selectively survives and multiplies in metastases and primary tumors with help of myeloid-derived suppressor cells (MDSC) and immune suppression in the tumor microenvironment (TME). 32 P was efficiently incorporated into the Listeria bacteria by starvation of the bacteria in saline, and then cultured in phosphorus-free medium complemented with 32 P as a nutrient. Listeria- 32 P kills tumor cells through both 32 P-induced ionizing radiation and Listeria-induced reactive oxygen species (ROS). The levels of 32 P and Listeria were studied in various normal and tumor tissues, at sequential time points after injection of mice with pancreatic cancer (syngeneic model Panc-02). We found that 32 P and Listeria predominantly accumulated in tumors and metastases, with their highest accumulation 4 hrs ( 32 P) and 3 days (Listeria) after injection. Listeria also penetrated the transgenic KPC (conditionally express endogenous Kras-G12D and p53-R172H mutant alleles) pancreatic tumors and metastases. This is remarkable since KPC tumors, like human tumors, exhibit a stromal barrier, which prevents most drugs from penetrating the pancreatic tumors. Therapeutic treatment with Listeria - 32 P resulted in a strong reduction of the growth of pancreatic cancer at early and late stages in Panc-02 and KPC mice. These results highlight the power of Listeria as new delivery platform of anticancer agents to the TME. Not only were therapeutic levels of radioactive Listeria reached in tumors and metastases but the selective delivery also led to minimal side effects.