Transforming Bladder Cancer Care: How Repurposing BCG and the TB Vaccine is Changing Treatment Strategies

Bacillus Calmette-Guerin (BCG): From Tuberculosis Vaccine to Bladder Cancer Treatment

What is Bacillus Calmette-Guerin?

Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine derived from a weakened strain of the Mycobacterium bovis bacterium, which is responsible for tuberculosis (TB). Developed by Calmette and Guérin in 1921, BCG has become the most widely administered vaccine globally. Its primary purpose is to prevent severe forms of tuberculosis, particularly in children, including tuberculosis meningitis and pulmonary tuberculosis in adults. Additionally, it offers protection against other mycobacterial diseases such as leprosy and Buruli ulcer. Recently, BCG has gained attention for its effectiveness in treating bladder cancer.

BCG as a Vaccine

The administration of BCG stimulates a dual immune response. Initially, the innate immune system activates, deploying macrophages, natural killer cells, and dendritic cells to neutralize the weakened bacteria. Following this, the adaptive immune system generates targeted T cells and B cells, which provide long-term protection against tuberculosis. This coordinated response is essential for the vaccine’s effectiveness in preventing severe tuberculosis cases.

BCG’s Transition to Cancer Immunotherapy

The journey of BCG from a tuberculosis vaccine to a cancer treatment began in 1929 when Dr. Pearl’s autopsy study uncovered a correlation between tuberculosis infections and reduced cancer rates. This sparked interest in the potential of bacterial products, including BCG, as cancer therapies. In the late 1800s, William B. Coley experimented with bacterial therapies, paving the way for immunotherapy.

By the late 1950s, studies by Lloyd Old revealed that BCG could enhance immune responses against tumors in mice, confirming its anti-cancer properties. Further research in the 1970s by Burton Zbar demonstrated that BCG had tumor-inhibiting effects, particularly when injected directly into tumors, emphasizing the importance of proximity between BCG and cancer cells.

The late 1960s and 1970s saw a surge of clinical trials exploring BCG’s effectiveness against various cancers, including leukemia and melanoma. A significant breakthrough occurred in 1975 when BCG was successfully used to treat bladder melanoma, leading to extensive research into its potential for bladder cancer therapy. Although its success was limited for other cancers, the FDA approved BCG as an immunotherapy for bladder cancer in 1990, marking it as the first cancer immunotherapy to receive approval.

Mechanism of Action in Bladder Cancer Treatment

Currently, BCG therapy involves administering a dose of Mycobacterium bovis BCG directly into the bladder via catheter, triggering a robust immune response aimed at targeting and destroying cancer cells. Early beliefs suggested that BCG activated the immune system against cancer; however, recent studies indicate that it also exerts direct toxic effects on cancer cells.

BCG induces apoptosis, a programmed cell death, and necrosis, a chaotic cell death. It generates oxidative stress within cancer cells, leading to their damage and eventual death. BCG attaches to both cancerous and healthy cells in the bladder, facilitated by a protein called fibronectin, which is more prevalent on cancer cells. Upon entry into the cells, BCG alerts the immune system, recruiting antigen-presenting cells (APCs) that display BCG fragments, effectively signaling for immune response.

This response mobilizes T cells that recognize the BCG-infected cancer cells, leading to a “cytokine storm.” This surge of immune activity attracts additional immune cells, such as macrophages and natural killer cells, to the tumor site to eliminate cancer cells.

Recent findings from researchers at Memorial Sloan Kettering have revealed that immune cells recognizing BCG fragments on tumor cells significantly contribute to the therapy’s effectiveness, increasing T cell infiltration in tumors and enhancing cancer cell destruction.

Side Effects of Bacillus Calmette-Guerin

As a vaccine, BCG is generally safe and does not typically cause severe complications. However, it is contraindicated for individuals with weakened immune systems, such as those with congenital immunodeficiency or HIV, and for adults in low TB prevalence areas.

While BCG is effective, it can lead to uncomfortable side effects, including:
– Irritated bladder
– Blood or debris in urine
– Pain or discomfort during urination
– Flu-like symptoms within 24-48 hours post-treatment
– Increased urgency and frequency of urination

Rare side effects may include:
– Cough
– Skin rash
– Fever and chills
– Joint or muscle pain
– Extreme fatigue
– Nausea or vomiting

Unanswered Questions Regarding BCG

Despite its successes, questions remain about BCG’s mechanisms and efficacy. Scientists are actively researching the biological pathways involved in BCG immunotherapy to enhance treatment personalization. Additionally, there is a significant portion of bladder cancer patients who do not respond to BCG treatment, prompting ongoing investigations into improving its efficacy.

While primarily utilized for tuberculosis and bladder cancer, researchers are exploring ways to optimize BCG immunotherapy for other medical conditions.

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-Guerin. Front Immunol. 2018;9:121. doi:10.3389/fimmu.2018.00121.
– Moliva JI, Turner J, Torrelles JB. Immune Responses to Bacillus Calmette-Guerin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?. Front Immunol. 2017;8:407. 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. 179(1), pp. 53–56. doi: 10.1016/j.juro.2007.08.122.
– Guallar-Garrido S, Julián E. Bacillus Calmette-Guerin (BCG) Therapy for Bladder Cancer: An Update. Immunotargets Ther. 2020;9:1-11. 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).