Bladder cancer is the fifth most common cancer in Canada, affecting approximately 12,000 Canadians each year. Often manifesting with visible blood in the urine, this malignancy is closely linked to factors such as age and smoking. Notably, bladder cancer is the most expensive cancer to treat due to its high recurrence rates.
The majority of patients (up to 80%) have non-muscle invasive bladder cancer which is when the tumor is confined to the outside layer of the bladder, yet to enter into the muscular layer. Currently, the therapeutic approach for intermediate and high-risk non-muscle invasive bladder cancer entails tumor removal and the administration of Bacillus Calmette-Guérin (BCG) treatment. BCG is a live attenuated form of Mycobacterium bovis. It is administered directly into the bladder via a catheter and leads to cancer cell death. But how did a bacterium, originally developed as a tuberculosis vaccine, become the gold standard for treating this type of bladder cancer?
BCG traces its roots to the ingenious work of Albert Calmette and Camille Guérin, two scientists at the Pasteur Institute in Lille, France. After 13 years of work, these scientists carefully manipulated the bacterium, diminishing its disease-causing potential. BCG gained popularity in Europe and later around the globe, making it the most widely used vaccine in the world.
Around the same era, American surgeon William Coley's ground-breaking experiments in bacterial preparations to combat cancers fueled the notion of stimulating the immune system for enhanced cancer cell killing. He treated hundreds of patients with “Coley’s Toxins”, a formulation made from heat-killed bacteria among other substances. Despite the relative lack of popularity, the idea of harnessing bacteria to activate the immune system and treat cancer persisted on the fringes of scientific exploration. This topic was covered in more detail in the accompanying blog post, Cancer Immunotherapy: A Tale as Old as Time, which you can read here.
Concurrent with these advances, there was a belief that tuberculosis protected against cancer based on autopsy observations. This led many researchers to explore BCG's potential in treating various cancer types, including bladder cancer. In 1976, Canadian physicians and scientists, Dr. Alvaro Morales, Dr. David Eidinger, and Dr. Andrew W. Bruce, published a ground-breaking study demonstrating that BCG, when administered weekly for six weeks, led to a remarkable 12-fold reduction in bladder cancer recurrence in patients. However, a question lingering in everyone's mind at that time was, “Why six weeks?”.
It was understood at that point that repeated administration of BCG was needed for a response, but the optimal frequency remained unknown. Anecdotally, the BCG vaccine from the Institut Armand Frappier (Montreal, QC), was packaged with six vials per box, prompting the use of a 6-week treatment protocol. Although purely a serendipitous decision, it was later proven to be the right choice. This milestone publication paved the way for two randomized clinical trials, ultimately resulting in the FDA approval of BCG for non-muscle invasive bladder cancer in 1990. Post-approval, researchers diligently delved into unraveling the mechanisms through which BCG mitigates tumor progression and recurrence. While the treatment regimen underwent modifications based on new data, BCG remained a pioneering example in the realm of cancer immunotherapy.
As bladder cancer remains the most expensive cancer to treat in Canada, the urgency for continued research is evident. The Canadian story in the treatment of superficial bladder cancer serves as an inspiring narrative, urging us to pursue further advancements in cancer care. The journey from a vaccine to a cancer therapy exemplifies the power of scientific exploration and collaboration, offering hope for continued progress in the fight against bladder cancer and beyond.
References:
Bladder cancer facts. Bladder Cancer Canada. (2022, April 27). https://bladdercancercanada.org/en/bladder-cancer-facts/
Lobo, N., Brooks, N. A., Zlotta, A. R., Cirillo, J. D., Boorjian, S., Black, P. C., Meeks, J. J., Bivalacqua, T. J., Gontero, P., Steinberg, G. D., McConkey, D., Babjuk, M., Alfred Witjes, J., & Kamat, A. M. (2021). 100 years of bacillus calmette–Guérin immunotherapy: From cattle to covid-19. Nature Reviews Urology, 18(10), 611–622.
Loughlin, K. R. (2020). William B. Coley. Urologic Clinics of North America, 47(4), 413–417.
Morales, A. (2017). BCG: A throwback from the stone age of vaccines opened the path for bladder cancer immunotherapy. The Canadian Journal of Urology, 24(3), 8788–8793.
Thiel, T., Ryk, C., Renström-Koskela, L., Steineck, G., Schumacher, M. C., Wiklund, N. P., & de Verdier, P. J. (2018). Intravesical BCG treatment causes a long-lasting reduction of recurrence and progression in patients with high-risk non-muscle-invasive bladder cancer. World Journal of Urology, 37(1), 155–163.