Cytokine-Secreting Probiotics for Cancer Immunotherapy

In the past, cancer diagnosis was associated with a horrible experience and a death sentence. The diagnosis of cancer has an enormous physical and mental impact for the patient and his family. For a long time chemotherapy was the main treatment for late stage cancer. Even though chemotherapy has saved many lives, many cancer patients do not respond to it or experience cancer relapse. Furthermore, chemotherapy affects not only cancer cells, but also healthy cells. General fatigue, indigestion and weakened immune system can reduce general health to a point of inability to stay employed, which affects financial and mental
health. Furthermore, global cancer cases are expected to rise in the future due to longer longevity, sedentary and unhealthy lifestyle and environmental pollutants. Therefore, the need for new and effective cancer treatments has never been higher.

Development of new types of treatments has achieved significant advances in curing certain types of cancers. Nowadays cancer treatment is focusing on targeted approaches, which would have stronger antitumor activity and lower systemic toxicities. Biological targeted therapy has shown great achievements for treating specific types of cancer, especially breast cancer. Furthermore, in the last decades there has been significant advancements in therapies that harness the immune system to fight cancer cells.

The main function of the human immune system is to protect our body from harm whether it is from external pathogens like bacteria and viruses or internal harm, such as cancer cells. Contrary to other types of cancer therapy, immunotherapy drugs are not directly toxic to cancer cells. Instead, these drugs activate the immune cells or direct them to recognize and kill abnormal cancer cells. Cancer immunotherapy is revolutionizing cancer therapy and emerging as first-line treatment strategy for several types of malignancies, including melanoma, nonsmall cell lung cancer and myeloma. Immunotherapy treatments include different strategies that help the immune system recognize and fight cancerous cells, such as checkpoint inhibitors, cancer vaccines, CAR-T cells and cytokines.

Cytokines are specific signaling proteins that orchestrate and promote immune cell activation. Cytokine immunotherapy involves systemic administration of high amounts of immune cell-activating cytokines. Although cytokine therapy has a lot of potential, it has been abandoned as a stand-alone treatment due to high toxicity, which comes from systemic administration of these drugs. This highlights the importance of local delivery of cytokines in order to obtain better therapeutic effects and avoid systemic toxicities. Local cytokine delivery can be achieved in different ways; however, a novel approach is to produce them in situ with Advanced Microbial Therapeutics (AMTs).

Bacterial-based immunotherapy strategies have re-surfaced after reports of specific bacteria colonizing tumors and affecting the immune response. These bacteria have the extraordinary ability to colonize tumors due to an abundance of nutrients from necrotic cancer cells and protection from immune cells due to the immunosuppressed tumor microenvironment. Recent advances in synthetic biology enables engineering of bacteria to produce AMTs with enhanced tumor colonization as well as production of therapeutics directly in the tumor microenvironment.

An advantage of using AMTs to deliver cytokines is that they can specifically colonize the tumor site and produce the drugs locally, therefore, minimizing systemic toxicities. This PhD project focused on establishing an AMT platform for intratumoral cytokine production using Escherichia coli Nissle 1917 probiotic bacteria and assessing their therapeutic potential in cancer immunotherapy.