Tumour. Cancer. *winces*. Whether you’re referring to the zodiac sign or the second leading global cause of death, these words would make your gut slightly churn. A disease that has taken so many lives, and is predicted to only claim more [1]. As scientists dig deeper into the cause of cancers, the agonizing side effects of chemotherapy, expensive surgeries, relapses, and resistance to existing drugs further complicate the situation. Naturally, scientists have been engrossed in looking for alternatives to curb this growing menace.
That’s when they stumbled upon one of the most bizarre findings ever, in the works of the 19th-century American bone surgeon William Bradley Coley. He had observed that upon injecting his patients with specific heat-inactivated bacterial mixtures (which were called “Coley’s toxin”), tumours significantly decreased, and even disappeared from the body! Coley’s toxin went on to be used in treating different types of cancer [2]. Its widespread use, however, was not approved by the FDA as Coley could not explain the exact mechanism behind the observation. Although Coley is today regarded as the “Father of Cancer Immunotherapy,” he was not the first person to observe this antagonistic relation between bacteria and tumours- the first document associating a type of “swelling” to infections dates to 2600 BC, by the Egyptian physician Imhotep [3]. In 1863, W. Busch conducted the first “clinical trials” when he transferred a cancer patient onto a bed previously occupied by a patient who had succumbed to a serious streptococcal infection [3]. He too was able to witness a regression of the tumour. Based on the foundation laid by these great minds, researchers carried out experiments that yielded highly promising results; the use of certain bacteria (such as Salmonella, Clostridium, and Listeria) in tumour therapy even made it to the Phase 1 clinical trials [3].
But how is it that bacteria, notable for causing a multitude of diseases in humans, is now being considered a potential cure for cancer?
Before we delve into the how-and-why, let’s talk about some properties of cancer. Tumours are a mass of abnormal cells that multiply uncontrollably. The centre of this mass often lacks blood supply, which makes it difficult for oxygen or any drugs to reach this area. As oxygen is vital for radiation to have its lethal effect [4], this region mostly resists usual treatment strategies and is also responsible for the dreaded cancer relapses. Another property of cancer cells that makes them so notorious is the ability to escape the vigilant check of our immune system called “immunosurveillance.” The reason behind this evasion of immunosurveillance has not been pinpointed; researchers speculate that the different mutations in the cancer cell lead to altered proteins [5], which could “mask” the cancer cell from the immune system.
And now for the protagonist- bacteria. Most of the bacteria that have shown promising results are those that are able to grow only in anaerobic (“obligate anaerobes”) or both aerobic and anaerobic conditions (“facultative anaerobes”). So even though they colonize the other organs of the body (that are aerobic), they are also found abundantly in the anaerobic regions in the tumour, an environment typically not found elsewhere in the body. Bacteria have been reported to thrive on the nutrients provided by dying tumour cells, and even have a direct destructive effect on them [6] [7]. Since these foreign bodies are (generally) devoid of any “masks” (also because our immune system is just so cool!) the immune cells promptly scour the body, recognize, and clear these microbial creepy-crawlies from our body. In this pursuit, the tumours housing these bacteria are exposed to the keepers of our body, and thus, provoking the immune cells against the “unmasked” tumour.
One must not forget that most of the genera of bacteria studied in tumour therapy such as Salmonella, Clostridium, Mycobacterium, and Listeria are major human pathogens. It is hence typical to think that injecting these bacteria into the body would lead to complications of its own. That’s where the process of “attenuation” comes into play [8]. In simple words, the bacteria are made weaker through genetic alterations, such that they aren’t potent enough to cause any infection, but can still trigger the immune system. By heating the bacterial suspension, Coley “attenuated” the microbes such that they would not pose a threat while still being able to achieve the desired tumour clearance.
The success of bacterial tumour therapy stands proudly on the limitations of conventional cancer therapy strategies. Bacterial tumour therapy is not specific to a certain type of cancer and has shown results against breast, prostate, gastric, and pancreatic cancers, amongst others. Self-propelled by the flagella, bacteria have high tumour penetration, and are highly specific to tumour cells, hence reducing the side effects. They can multiply within the tumour, and at the same time be controlled using antibiotics [9]. Bacteria can be easily manipulated to carry drugs, toxins, enzymes, etc., to the impenetrable regions of the tumour [10]. Some bacteria are engineered to be fluorescent to be used in tumour imaging [11].
Every coin has two sides. Bacteria mediated tumour therapy, in all its glory, is not efficient enough to be used on its own. In fact, no strategy has achieved tumour clearance when used solo. Bacterial therapy, when coupled with radiotherapy and/or chemotherapy gives the best results. Attenuation is vital in controlling the inherent toxicity of pathogens. At the same time, “over-attenuation” must be avoided; the Phase 1 clinical trials were not as successful as expected because the bacteria were weakened so much that the immune system could not be triggered [12]. Nevertheless, the potential that this strategy has cannot be sidelined. It is thus crucial to explore this possible weapon in the battle against cancer.
Who would have thought that microscopic mighty beings capable of causing serious diseases could one day be used to treat another life-threatening disease? Well, my friend, that comes under the many wonders of science!
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