[Malithi Weerakkody]

Bacteria make people sick, one would say. Yes they do. However, they can also make people better. For almost a hundred years, scientists have known the potential of using bacteria to alleviate certain cancers. Now, with most of the other available anticancer therapies proving inefficient, the focus is back on the ability of these tiny bugs to cure cancers.

The History of Bacterial Anticancer Therapy

The German physicians W. Busch and F. Fehleisen and the American physician William Coley were the first people to observe that bacterial infections reduced cancers in patients. They independently noticed that some of their patients suffering from cancers recovered after being infected by the bacterium Streptococcus pyogenes. In the late 1800s, Doctor Coley developed a vaccine using the dead cells of two bacterial species, S. pyogenes and Serratia marcescens and that successfully treated various cancers. He also prepared 'Coley's toxins' - toxic derivatives of bacteria-as anticancer treatments which were the only systemic anticancer therapy available until the 1930s. Subsequently, novel treatments such as radiotherapy, chemotherapy, and removal of cancer tissues by surgery were introduced and the interest was lost on the bacterial therapy.

Using Bacteria to Treat Cancers

The potential of bacteria as anticancer agents lies within the ability of certain strict or facultatively anaerobic bacteria to selectively colonise tumour tissues. Large tumours mostly contain necrotic and hypoxic areas in the middle, providing ideal growth conditions for the growth of these bacteria. Since they can’t thrive in oxygen-rich environments, the bacteria do not infect healthy tissues thereby making them safe to the normal tissues.

Bacteria, either live or attenuated, can be used as oncolytic agents, i.e. to lyse the tumours directly, or they can be used as delivery vehicles to transport therapeutics to the tumours. These bacterial vectors, after being genetically altered, can transport anticancer drugs, cytotoxic peptides, therapeutic proteins or prodrug converting enzymes into the target site. Furthermore, bacterial toxins and bacterial spores also have a potential as antitumour agents. Furthermore, bacteria can act as immunotherapeutic agents, stimulating the immune system of the host against the cancer cells.



Bacterial Spore-Mediated Cancer Therapy

Spores of these anaerobic bacteria can only germinate and multiply in environments devoid of oxygen. These spores, when injected systemically, will remain dormant in healthy oxygen rich cells and become active within the anaerobic and necrotic cancer tissues. This strategy makes these spores ideal for anticancer therapies. Once within the tumour microenvironment, these spores can activate and proliferate thus colonising the tissues with the desired bacterial species.



Bacteria as Direct Oncolytic Agents

Some bacteria can lyse the tumours upon infecting them. However, these bacteria do not completely destroy the tumour, thus necessitating the combination of bacterial therapy with other anticancer treatments such as radiotherapy, radioimmunotherapy, and chemotherapy.

Some bacteria are known to enhance the effectiveness of chemotherapeutic agents such as liposome-encapsulated drugs by facilitating their release within the tumours by liposomase.



Bacteria as Tumour-Targeting Vehicles

Bacteria can be genetically modified to deliver a therapeutic gene to the tumour cells. Once within the target tissue, gene expression will occur in the bacteria thus producing the required protein that destroys the cancers. These proteins can be anticancer proteins, therapeutic proteins or prodrug converting enzymes.

In the bacteria-mediated prodrug therapy (also known as suicide gene therapy), bacteria carry a gene coding for an enzyme that converts a prodrug-which is non-toxic- into a toxic drug. These bacteria, favouring the anaerobic and necrotic conditions of the tumour microenvironment, start proliferation and growth within the tumours. Since their growth is limited to the tumour cells only, the enzyme is produced exclusively in the cancers. The prodrug is supplied systemically and within tumour, it is converted into the tumouricidal drug by the enzyme.



Alternatively, these bacteria can be genetically engineered to express cytotoxic enzymes such as cytokines that will directly destroy the tumour cells.

Bacteria in Cancer Immunotherapy

Bacteria can be used to enhance the recognition of tumour cells by the immune system. Tumour cells, essentially being parent’s own cells, fail to evoke sufficient immune responses in the host to be destroyed by the immune system. However bacteria, though stripped off their pathogenicity factors, can stimulate the immune system thus enhancing the antigenicity of the tumours. Bacteria selectively invade the cancer tissues and present bacterial antigens thus being targets for the host immune system. The host immune system then destroys the bacteria infected tumour cells which would have otherwise evaded the attack.

Bacterial Toxins as Anticancer Agents

Bacterial toxins kill cells or affect cellular proliferation at lower levels. These toxins, after modifying their cellular affinities so that they will bind only to the cancer cells, can be used to control cancers. These toxins can be made safe to the healthy cells by either coupling them with a substance such as antibodies that bind specifically with the cancer cells or by genetically altering their cell-binding properties.

Combined Bacteriolytic Therapy (COBALT)

COBALT uses bacteria- directed anticancer treatments along with other conventional therapies such as chemotherapy or radiotherapy. This strategy thus far has been shown to significantly increase the effectiveness of oncolysis than the individual treatments.

Another prospective anticancer treatment combining radiotherapy and bacterial therapy has also been discovered recently. This treatment using radioactive Listeria-i.e. an attenuated species of Listeria monocytogenes labelled with a radioactive Rhenium isotope- has reported to successfully improve pancreatic cancer.

Benefits and Limitations

Major advantage of using bacteria and bacterial derivatives as anticancer treatments is their selectivity towards the cancerous cells. Other therapeutic alternatives such as chemotherapy and radiotherapy are non-selective, thus damaging healthy tissues as well as cancer tissues. Moreover, the bacteria are easy to produce in mass scale thus reducing the cost of production of drugs.

However promising, bacteria-mediated anticancer treatment is not without its own limitations. One of the major drawbacks is the ability of these bacteria to cause diseases at the doses required for an effective tumouricidal effect. Even after attenuation, some studies report the death of the animals after administrating these bacteria. Another main problem is incomplete lysis of the tumours by the bacteria thus making it necessary for a secondary alternative treatment option. Furthermore, these anaerobic bacteria can only target large solid tumours where there are anaerobic conditions favourable for their growth. Small non-necrotic secondary tumours are out of their reach, and as a result, there is a chance of the cancer being spread through these metastases.

Future Prospects

Despite these hindrances, the bacterial anticancer therapy shows great potential towards the future. With the advent of genetic engineering and synthetic biological approaches, there is hope that it will be possible to come up with an efficient, safe and effective bacteria-mediated cancer treatment.



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Sources

1. Patyar, S., Joshi, R., Byrav, D. P., Prakash, A., Medhi, B., & Das, B. K. (2010). Review Bacteria in cancer therapy: a novel experimental strategy. J Biomed Sci, 17(1), 21-30.
2. Umer, B., Good, D., Anné, J., Duan, W., & Wei, M. Q. (2012). Clostridial spores for cancer therapy: targeting solid tumour microenvironment. Journal of toxicology, 2012.