Bacillus Calmette-Guerin (BCG) is a vaccine historically used to prevent tuberculosis (TB), but it is now being used to fight against bladder cancer. How does it work, and how has it been repurposed to treat such a different condition?
What is Bacillus Calmette-Guerin?
Bacillus Calmette-Guerin is a live attenuated vaccine, containing a weakened form of the bacterium Mycobacterium bovis that causes tuberculosis. Calmette and Guérin first developed it in 1921, and it is now the most widely used vaccine in the world.1-3
Its job is to prevent severe forms of tuberculosis in children, like tuberculosis meningitis, and to protect against pulmonary tuberculosis, the most common version in adults.3 The BCG vaccine can also protect against leprosy and Buruli ulcer, these are both caused by mycobacteria-similar organisms to the bacterium that causes TB. More recently and perhaps surprisingly, the BCG has successfully been repurposed as a treatment for bladder cancer.1
BCG as a vaccine
Injecting a weakened form of bacteria into the body stimulates a dual immune response. The body’s initial defense, the innate immune system, quickly mobilizes its macrophages, natural killer cells and dendritic cell soldiers to eat and neutralize the weakened bacteria within the vaccine. Then, the adaptive immune system kicks in, creating a targeted and long-lasting defense by generating specific T cells and B cells that recognize and kill the tuberculosis bacteria in the future. This orchestrated response is the key to the vaccine’s ability to provide lasting protection against severe forms of tuberculosis.4
When did the BCG turn into a cancer immunotherapy?
In 1929, Dr. Pearl’s autopsy study at Johns Hopkins revealed a surprising link between tuberculosis infection and lower cancer rates, igniting conversation about a potential connection.5 This curiosity was further fueled by observations in the late 1800s of cancer regression in patients with bacterial infections, prompting William B. Coley to experiment with bacterial products (like Bacillus Calmette-Guerin) as a novel cancer treatment in 1893.5 This laid the groundwork for immunotherapy.
Fast forward to the late 1950s, Lloyd Old’s groundbreaking studies showed that BCG could boost the immune response against tumors in mice, highlighting its indirect anti-cancer properties.5 This was further confirmed in the 1970s by Burton Zbar, whose research demonstrated BCG’s tumor-inhibiting effects, especially when injected directly into tumors. Zbar emphasized the importance of close contact between Bacillus Calmette-Guerin and tumor cells for optimal results.5
The late 1960s and 1970s marked a period of hope and excitement as early clinical trials showed promising results for Bacillus Calmette-Guerin in treating various cancers, including leukemia and melanoma. A major breakthrough came in 1975 when BCG successfully treated melanoma in the bladder, prompting further research into its potential for bladder cancer therapy.5 Disappointingly, while BCG initially showed promise, its success in treating other cancers proved limited. This led to its replacement with more effective therapies for those illnesses.
The FDA approved BCG as bladder cancer immunotherapy 1990, making it the first cancer immunotherapy to be approved.5,6 It is now a standard treatment for early-stage bladder cancer, demonstrating the power of immunotherapy in harnessing the body’s immune system to fight this disease.
How does it treat bladder cancer?
Today, a single dose of Mycobacterium bovis BCG immunotherapy is delivered directly into the bladder through a catheter to stimulate a strong immune response within the bladder, targeting and destroying cancer cells.1
Scientists initially believed that BCG activated the immune system to fight cancer, but recent studies developed a clearer picture: it has direct toxic effects on cancer cells.7
It turns out that BCG triggers the demise of cancer cells through a programmed self-destruction process called apoptosis and a more chaotic form of cell death called necrosis.7 It also acts like a bomb inside cancer cells by sparking the production of harmful molecules that react with each other, overwhelming the cell’s ability to cope. This is called oxidative stress, and it leads to damage and death of the cancer cell.
So how does a BCG bacterium find and take out cancer cells but not healthy cells? When it is administered into the bladder, BGC bacteria attach to both cancer and healthy cells. This attachment is made possible by a protein called fibronectin. It is present on both cell types, but it’s found in higher amounts on cancer cells compared to healthy bladder cells. Once attached, BCG bacteria force their way into the cell and make themselves at home. Once inside the cells, the cell’s own machinery notices the unwelcome intruders and sounds the alarms.7
Responding to the call, antigen-presenting cells (APCs) are recruited to the scene of the break in, they recognize Bacillus Calmette-Guerin as an intruder, and display its fragments on their surface. Acting like “criminal found” alarms for the immune system, these APCs call for backup. When patrolling T cells see the alarms, it is their time to fight. They begin to multiply and differentiate into specific types of T cells that can directly kill the cells displaying the fragment (in this case, cancer cells infected with BCG).7 The activated immune cells release a flood of cytokine soldiers, creating a “cytokine storm.” This storm rallies other immune cells like macrophages, neutrophils, and natural killer cells, which swarm the tumor site and destroy cancer cells.
This immune system defense strategy is typically how vaccines work against infectious diseases. But in 2020, researchers from Memorial Sloan Kettering published findings, adding that immune cells that recognize the Bacillus Calmette-Guerin “criminal found” alarms are not solely responsible for the therapy’s effect against cancer.8 Rather, it’s immune cells that recognize fragments on tumor cells that make the difference. This causes a flood of T cells in the tumor itself, allowing immune cell soldiers to kill the cancer at the site.
Side effects of Bacillus Calmette-Guerin
As a vaccine, Bacillus Calmette-Guérin is fairly safe and not associated with any severe complications.1 But it should not be given to:
- Individuals with weakened immune systems: those with congenital immunodeficiency, HIV infection, or those taking medications like tumor necrosis factor-alpha blockers or corticosteroids, which suppress the immune system.
- Adults with HIV infection living in areas of low TB prevalence
As an immunotherapy, Bacillus Calmette-Guérin can cause uncomfortable side effects.9
Possible side effects:
- Irritated bladder
- Blood or debris in the urine
- Pain or discomfort when passing urine
- Flu-like symptoms 24-48 hours after treatment
- Passing urine more often and more urgently than usual
Rare side effects:
- Cough
- Skin rash
- Fever and chills
- Joint or muscle pain
- Feeling extremely tired
- Feeling sick or vomiting
Unanswered questions
Do scientists understand exactly how it works? While the exact biological mechanisms of Bacillus Calmette-Guérin immunotherapy remain partially understood, scientists are continually working to unravel its complexities. As with many other therapies, ongoing research helps find more details about how it effectively fights cancer. With this knowledge, they will be able to specifically tailor treatments to patients.
Does it work for everybody? No, despite Bacillus Calmette-Guérin’s incredible and ongoing success as an immunotherapy, there is still a larger percentage of bladder cancer patients who do not respond to the treatment. Scientists are working on figuring out why that is and how to improve its odds of success.
What other uses does it have? As of now, it is primarily used for tuberculosis and bladder cancer, but scientists are trying to uncover ways to optimize Bacillus Calmette-Guérin immunotherapy for other illnesses.
References
- Okafor, C.N., Rewane, A. and Momodu, I.I. (2023) ‘Calmette-Guerin Bacillus’, StatPearls [Preprint]. doi:10.1007/springerreference_37813.
- Vanderslott, S. et al. (2024) Vaccination, Our World in Data. Available at: https://ourworldindata.org/vaccination (Accessed: 13 June 2024).
- Nieuwenhuizen NE, Kaufmann SHE. Next-Generation Vaccines Based on Bacille Calmette-Guérin. Front Immunol. 2018;9:121. Published 2018 Feb 5. doi:10.3389/fimmu.2018.00121
- Moliva JI, Turner J, Torrelles JB. Immune Responses to Bacillus Calmette-Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?. Front Immunol. 2017;8:407. Published 2017 Apr 5. doi:10.3389/fimmu.2017.00407
- Herr, H. W. and Morales, A. (2008) ‘History of Bacillus Calmette-Guerin and Bladder Cancer: An Immunotherapy Success Story’, Journal of Urology. WoltersKluwer, 179(1), pp. 53–56. doi: 10.1016/j.juro.2007.08.122.
- Guallar-Garrido S, Julián E. Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer: An Update. Immunotargets Ther. 2020;9:1-11. Published 2020 Feb 13. doi:10.2147/ITT.S202006
- Han, J. et al. (2020) ‘Mechanisms of BCG in the treatment of bladder cancer-current understanding and the Prospect’, Biomedicine & Pharmacotherapy, 129, p. 110393. doi:10.1016/j.biopha.2020.110393.
- Antonelli, A.C. et al. (2020) ‘Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-γ signaling’, Proceedings of the National Academy of Sciences, 117(31), pp. 18627–18637. doi:10.1073/pnas.2004421117.
- BCG into the bladder (2023) for non muscle invasive bladder cancer | Cancer Research UK. Available at: https://www.cancerresearchuk.org/about-cancer/bladder-cancer/treatment/non-muscle-invasive/bcg (Accessed: 14 June 2024).
