Mechanisms of BCG immunotherapy and its outlook for bladder cancer

Abstract

BCG immunotherapy is the gold-standard treatment for non-muscle-invasive bladder cancer at high risk of recurrence or progression. Preclinical and clinical studies have revealed that a robust inflammatory response to BCG involves several steps: attachment of BCG; internalization of BCG into resident immune cells, normal cells, and tumour urothelial cells; BCG-mediated induction of innate immunity, which is orchestrated by a cellular and cytokine milieu; and BCG-mediated initiation of tumour-specific immunity. As an added layer of complexity, variation between clinical BCG strains might influence development of tumour immunity. However, more than 40 years after the first use of BCG for bladder cancer, many questions regarding its mechanism of action remain unanswered. Clearly, a better understanding of the mechanisms underlying BCG-mediated tumour immunity could lead to improved efficacy, increased tolerance of treatment, and identification of novel immune-based therapies. Indeed, enthusiasm for bladder cancer immunotherapy, and the possibility of combining BCG with other therapies, is increasing owing to the availability of targeted immunotherapies, including checkpoint inhibitors. Understanding of the mechanism of action of BCG immunotherapy has advanced greatly, but many questions remain, and further basic and clinical research efforts are needed to develop new treatment strategies for patients with bladder cancer.

Key points

  • BCG immunotherapy is the gold-standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) to prevent disease recurrence and progression.

  • BCG induces a robust innate immune response over several weeks that leads to lasting antitumour adaptive immunity.

  • Different BCG substrains are in clinical use around the world, but whether these strains have varying efficacies in the induction of tumour immunity is unclear.

  • Efforts to improve BCG immunotherapy have largely failed, and to date, no existing therapy outperforms BCG for treatment of high-risk NMIBC.

  • New approaches, which incorporate novel immunotherapies such as checkpoint inhibitor antibodies, might successfully synergize with BCG to improve patient outcomes.

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Fig. 1: A brief history of BCG and cancer.
Fig. 2: BCG-induced tumour immunity.
Fig. 3: Immune checkpoint molecule inhibitors being tested in NMIBC.

Figure adapted from ref.168, Macmillan Publishers Limited.

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Acknowledgements

The authors thank Y. Neuzillet (Department of Urology, Hopital Foch, Suresnes, France) for the critical reading of this manuscript. The authors also thank the French Association of Urology (AFU) and LabEx ImmunoOnco for funding support for research on BCG and non-muscle-invasive bladder cancer.

Review criteria

A systematic search was performed in the PubMed and Cochrane databases. Manuscripts not available as full text were excluded. The principal keywords used for publication selection were “BCG”, “immunotherapy”, “intravesical”, “instillation”, “NMIBC”, and “mechanism of action”. The following specific keywords and associations were added using [AND] or [OR]: “attachment”, “internalization”, “immune response”, “innate”, “adaptive”, “immune cell”, “cytotoxic”, “antitumour”, “side effects”, “BCG vaccination”, “BCG strain”, and “checkpoint inhibitors”. Manuscripts that were accessible in English or French were selected, including preclinical studies and clinical trials, systematic reviews, and meta-analyses, in addition to the latest versions of the European and French Associations of Urology Guidelines. To perform an exhaustive search, no publication year limit was used, and the last search was updated in November 2017.

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Both authors researched data for the article, made a substantial contribution to discussion of content, and wrote, reviewed, and edited the manuscript before submission.

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Correspondence to Molly A. Ingersoll.

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Pettenati, C., Ingersoll, M.A. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol 15, 615–625 (2018). https://doi.org/10.1038/s41585-018-0055-4

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