Modified bacteria produce tetanus toxin, which is utilized to treat fatal pancreatic cancer  

Pancreatic cancer is a highly malignant tumor of the digestive tract that is difficult to diagnose and treat, and the morbidity and mortality rates have risen dramatically in recent years. Pancreatic cancer is at an advanced stage when diagnosed when cancer cells have spread and are hard to control. The most frequent pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic malignancies.

Immune checkpoint inhibitors have had exceptional success in many cancers and have even transformed the cancer therapy landscape, yet this treatment has not benefitted pancreatic cancer patients. One reason for this is that pancreatic cancer is a "cold tumor" that the immune system is unable to recognize and eliminate.

Recently, researchers from the Albert Einstein College of Medicine published a research paper in the journal Science Translational Medicine entitled: Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice. The researchers devised a novel therapeutic strategy for infecting pancreatic cancer model mice with genetically modified Listeria monocytogenes expressing tetanus toxin. These Listeria monocytogenes remain in tumor tissue and are cleared by healthy tissue, activating T cells to kill the tumor, which, when combined with chemotherapeutic agents like gemcitabine, rapidly cleared pancreatic cancer cells, reduced cancer metastasis by 87%, and dramatically extended life.

Utilizing tetanus vaccine

The great majority of people were immunized against tetanus as children, using a tetanus toxoid derived from the toxin produced by the bacterium Mycobacterium tetani. Tetanus toxoid-induced memory T cells circulate in the bloodstream for life, and patients who receive this vaccine will have a strong immune response if they are later exposed to tetanus toxoid produced by the tetanus bacterium.

The researchers inoculated pancreatic cancer model mice with the same tetanus vaccine used in humans, then incorporated the gene encoding the tetanus toxin into the non-pathogenic Listeria monocytogenes, a bacterium capable of rapidly infecting human cells and spreading within tissues. The modified Listeria was then put into pancreatic cancer model mice that had already been immunized with the tetanus vaccine.

By infecting pancreatic cancer cells with bacteria that deliver tetanus toxin into the cells, Dr. Gravekamp and her colleagues effectively elicited an effective and specific immune response against pancreatic cancer cells.

Exploiting the suppressive environment of cancer

Except in the tumor microenvironment, Listeria monocytogenes are extremely weak and readily eliminated by the immune system in humans and animals. So this therapy technique actually takes advantage of the suppressive tumor microenvironment of pancreatic cancer, where these Listeria may live for a long time in the tumor area of pancreatic cancer, whereas they are promptly eliminated by the immune system in healthy tissues.

T-cell responses could be improved further by administering low doses of gemcitabine, a chemotherapeutic drug that lowers immunosuppression. This treatment reduced the size of pancreatic tumors in mice by an average of 80% and cancer metastasis by 87%, and treated mice lived 40% longer than untreated mice.

In addition, the team said the treatment could be used to treat other types of cancer beyond pancreatic cancer, such as ovarian cancer, where immunotherapy is currently ineffective.