Abstract
Genetic mutations have been progressively introduced to BCG by repeated serial passage over many decades of its culture and global dissemination. Thus, marked differences exist in the phenotype, antigenicity, reactogenicity, and clinical characteristics of the numerous substrains of BCG currently in use for bladder cancer immunotherapy. These differences influence proposed mycobacterial antitumour mechanisms and toxicity, potentially resulting in variations in clinical efficacy and adverse effects. However, although there is evidence of substrain-related differences in the clinical efficacy of BCG as a tuberculosis vaccine, evidence of an effect on bladder cancer immunotherapy remains elusive, owing to the lack of appropriately powered head-to-head comparative clinical trials, the nonstandardization of BCG manufacture, and variation in treatment protocols—possibly itself a response to underlying substrain differences. Advances in our understanding of mycobacterial genetics, structure and function, and host–pathogen interactions might explain differences in clinical practice and outcomes. These advances are guiding the identification of biomarkers for reactogenicity and efficacy, and the rational design of immunotherapeutic strategies to eliminate the use of live bacilli for bladder cancer therapy.
Key Points
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Outcome of BCG immunotherapy for bladder cancer depends upon key host–pathogen interactions, which might be influenced by both human and bacterial genetics
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BCG is not a defined strain but a family of regional substrains with marked genetic differences that have developed during manufacture and global dissemination
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Differences in phenotype, antigenicity, reactogenicity, and clinical characteristics of BCG substrains have been observed during their use as a tuberculosis vaccine
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Differences in bladder cancer outcomes between BCG substrains have been reported, but owing to the paucity of appropriately powered clinical trials the significance remains unconfirmed
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Multiple dose levels, number of doses, and dosing schedules exist for bladder cancer BCG therapy, which complicates comparison of clinical trial outcomes with different strains
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Appropriately powered head-to-head clinical trials using BCG substrains manufactured under current good manufacturing practice are required to determine if certain strains offer better efficacy or reduced reactogenicity for bladder cancer
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Change history
19 May 2015
In the introduction of the originally published article, the names of the BCG substrains involved in recent shortages in BCG supply were transposed. The error has been corrected for the HTML and PDF versions of the article.
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All authors researched data for the article and contributed to the discussion of content. C. Gan and D. J. M. Lewis wrote the article. All authors reviewed the manuscript before submission.
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Gan, C., Mostafid, H., Khan, M. et al. BCG immunotherapy for bladder cancer—the effects of substrain differences. Nat Rev Urol 10, 580–588 (2013). https://doi.org/10.1038/nrurol.2013.194
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DOI: https://doi.org/10.1038/nrurol.2013.194
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