Bacterial Fortification for Cancer Therapeutics

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Bhavuk Garg

Cancer treatment options have undergone multiple strategic shifts over the course of the last century starting with resection and moving to chemotherapy, immunotherapy, and chemical inhibitors. Major challenges faced by many therapeutics are adverse toxic reactions inflicted on the patients and the development of therapeutic resistance due to high mutability and adaptability of cancer cells. Greater understanding of human biology and cancer cell mechanisms have led to effective therapies with reduced toxicity and adverse events.

In the spate of molecular interventions against cancer, adoption of microorganisms as a potential therapeutic, especially bacteria against cancers, have been a neglected area of study. Our understanding of bacteria dates back centuries. Mechanistic adaptations to control their molecular and genetic function have turned them to factories and logistic carriers. Leveraging these molecular robots and arming them with therapeutics is a new paradigm of active research for anticancer therapeutics.

Bacteria, such as Salmonella, Listeria, and Clostridium spp., have inherent properties that enable them to target, penetrate, proliferate, and shrink solid tumors. The tumor microenvironment (TME) is often hypoxic (oxygen poor) which alters the metabolic profile of tumor cells. However, this hypoxic environment also allows these bacteria to thrive and execute cytotoxic activity associated with these pathogens. Microbiome research has led to greater understanding of the symbiotic relationship of bacteria and the human body which presents an opportunity in alternative therapeutics. S. typhimurium is chemo-attracted to the metabolites produced by quiescent cancer cells (cancer cells that are reversibly suspended in G₀ phase with the ability to re-enter the cell cycle and initiate tumor growth, and, ultimately, cancer recurrence and metastasis) within the TME where it proliferates and kills cancer cells by triggering cell death by apoptosis and necrosis. Listeria infects tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which migrate to the tumor site and ameliorates tumor burden by inducing cytotoxic response through T-Cells and Natural Killer cells. Similarly, Clostridium spp. which survive in oxygen-poor environments in tumors secrete exotoxins that damage the membrane structures of cancer cells and disrupt essential cellular functions.

Furthermore, bacteria have been engineered to act against tumors as chassis for delivery of drugs, immunomodulators, DNA and gene silencers, and enhancement of targeted bacteria binding to tumors. These may be nanobodies, peptides or antigens to elicit an adjusted immune response, such as bacteria expressing CD47, CTLA and PD1 (These molecules plays an integral role in various immune suppression responses as well as autoimmunity, either by suppressing phagocytosis by CD47 or inhibition of T cell activity by CTLA and PD1) nanobodies, flagellin molecules or cytokines which triggers immune response.  Peptides acting as angiogenesis modulators such as tumstatin and endostatin etc. or cytotoxic agents such as cytolysin A, α-haemolysin, TGFα–PE may be secreted by the engineered bacteria to bring about desired tumor degradation. 

Considering the outstanding progress in bacterial maneuverability, its admission as a therapeutic agent has been a slow and everlasting process. Use of BCG (Bacillus Calmette–Guerin) as a therapy against bladder cancer is the only case of clinical approval of  bacteriotherapy. BCG is used as an immunomodulator due to the antigens in the attenuated vaccine which is attributed to its induction of cytokines such as interleukin 2 and interferon gamma. There are a few potential reasons precluding execution of  bacteria as therapeutic agents. One is concern about the uncontrollable growth and spread of engineered bacteria in the patient. Though antibiotic treatment is a possibility in such a scenario, safety concerns still remain. Secondly, release of live biotherapeutic products through human excretion and into wastewater systems is a problem of which a solution has yet to be found. Lastly, the apprehension about horizontal gene transfer of antibiotic resistant gene-bearing plasmids from genetically modified therapeutic bacteria to other microorganisms in the patient or the environment remains a concern of bacterial therapeutics.

Ongoing clinical trials of bacteriotherapies alone and in combination with conventional and immunotherapies indicate their high potential and advancement in sorting out regulatory concerns. 

Edited by Hannah Young

Header Image: Colorized SEM image of E. coli, Wikimedia commons