An Immunotherapy Success Story: BCG and Bladder Cancer
Bacillus Calmette-Guerin (BCG) therapy of bladder cancer is the most successful immunotherapy used against any established human neoplasm. Although how BCG works in the bladder is still being defined, it is clear that BCG orchestrates a vigorous immune response involving sensitized T-lymphocytes, activated macrophages and their cytokines that interact to kill and prevent growth of cancer cells. Instilled into the bladder, BCG eradicates existing tumors, reduces the frequency of tumor recurrences, delays stage progression to invasion and improves survival over other local treatments. How did BCG, a vaccine used to prevent tuberculosis in much of the world’s population, become standard therapy of one of the most prevalent cancers in man? It is a remarkable story, marked by purposeful scientific discovery and serendipitous observation that culminated in sound experimental and clinical investigation.
Discovery and development of the BCG vaccine date back 100 years. In 1908, Albert Calmette, a bacteriologist, and Camille Guerin, a veterinarian, working together at the Pasteur Institute in Lille, France began their life-long quest to develop a TB vaccine against the scourge of tuberculosis. By 1915, they had administered an early form of the strain to several cows, demonstrating protection against TB.
Tuberculosis was noted to have antitumor effects early in the 20th century. In 1929, Pearl, in an autopsy study at the Johns Hopkins Hospital in Baltimore, reported a lower frequency of cancer among patients with tuberculosis. Pearl concluded that some mutual antagonism existed between TB and cancer, although he was unable to explain its basis. However, the link between tuberculosis and cancer was made.
The possible use of BCG as cancer therapy began with the landmark studies in the late 1950s by Lloyd Old at the Sloan-Kettering Institute in New York and provided the first direct evidence that BCG had antitumor effects.
The clinical use of BCG as cancer therapy began in 1969; the early reports created enormous interest in BCG, and clinical trials flourished using BCG against lung, prostate, colon and kidney cancers. Their promise was not fulfilled, and BCG was soon replaced by more effective therapy. The notable exception was bladder cancer.
Coe and Feldman demonstrated a strong delayed hypersensitivity reaction to BCG in the guinea pig bladder. Zbar established the criteria for successful BCG therapy. Based on these studies, Alvaro Morales, urologist in Canada, had the foresight to try topical BCG in the bladder. Morales devised the original BCG protocol against bladder tumors in 1972 and in 1976 he published the first use of intravesical BCG against superficial bladder cancer. In 1978, Morales’ encouraging results based on only seven patients spawned the NCI to fund two randomized controlled trials to test the effectiveness of the combined BCG regimen against superficial bladder tumors. In 1990, after local side effects and systemic toxicity were defined in more than 2,500 cases pooled worldwide, the Federal Drug Administration approved the general use of intravesical BCG in patients with superficial bladder tumors.
Thirty years after the first report, BCG therapy remains the recommended standard treatment of high-grade noninvasive bladder cancer. Concern about genetic drift and altered immunogenicity of the bacterium after years of subculture at various facilities has not emerged as a significant problem. Although the dose, frequency and duration of treatments continue to be subjects of debate, BCG therapy has stood the test of time, proved to be superior to other intravesical agents, and favorably altered the natural history of noninvasive bladder tumors. Over the past three decades, many patients have had their bladders spared, quality of life preserved and lives saved.