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

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). 32P was efficiently incorporated into the Listeria bacteria by starvation of the bacteria in saline, and then cultured in phosphorus-free medium complemented with 32P as a nutrient. Listeria-32P kills tumor cells through both 32P-induced ionizing radiation and Listeria-induced reactive oxygen species (ROS). The levels of 32P 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 32P and Listeria predominantly accumulated in tumors and metastases, with their highest accumulation 4 hrs (32P) 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 -32P 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.

Immunotherapy with Listeria reduces metastatic breast cancer in young and old mice through different mechanisms

“…In another study we also found that higher doses of Listeria significantly reduced tumor growth in a pancreatic cancer model. 36 In addition, Listeria survives better in a hypoxic environment, 37 and metastases are known to be more hypoxic than primary tumors.…”

Bugs as Drugs, potential self-regenerated innovative cancer therapeutics approach for global health

“…To activate the immune system, Salmonella expressing a "foreign" antigen (Vibrio vulnificus flagellin B (FlaB) was used to induced tumor suppression, bacterial colonization which is associated with TLR5-mediated host reactions and to activate the immune system against tumors harboring this Salmonella [10]. Listeria monocytogenes was engineered to deliver isotopes for targeted radiotherapy [5,11] and tumor-specific antigens enabling activating tumor-specific cytolytic T lymphocytes (CTL) inducing long-lasting anti-tumor-specific CTL responses. However, despite recent progress, many scientific gaps remain, and microbial-based cancer therapy is scientifically and clinically a very challenging field.…”

White paper on microbial anti-cancer therapy and prevention

“…Immune-cell-targeting bacteria, such as Listeria monocytogenes, can reduce tumor mass by delivering radioactivity. For example, 188-rhenium has been coupled to Listeria through anti-Listeria antibodies and shown to be effective against mice with pancreatic cancer [ 113 , 114 ]. Bacteria can also be engineered to deliver siRNA.…”