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.

Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches

“…In a mouse model study, depletion of neutrophils abolished the therapeutic effect of BCG by diminishing monocyte and CD4+ T cell infiltration in the bladder . However, it is yet to be verified if neutrophils are essential in BCG‐induced immunity in human bladder cancer . In a mouse model, depletion of NK cells also reduced efficacy of BCG immunotherapy .…”

“…Another 5‐year follow‐up study of 262 patients, also demonstrated that intravesical BCG significantly prevented recurrence compared to doxorubicin (63% versus 87% recurrence rate) . In 1990, the FDA approved intravesical instillation of BCG for NMIBC treatment, which was considered as a breakthrough cancer therapy .…”

“…While BCG has been FDA approved for nearly three decades and many mechanistic studies have been carried out, the mechanisms of BCG‐induced immunotherapeutic effect are still not fully understood due to the multiple biological aspects involved, including the innate and adaptive immune systems. There are review articles focusing on bladder cancer BCG therapeutic mechanisms . Here we summarise key immune response factors that are involved.…”

“…BCG induces infiltration of neutrophils and mononuclear cells into the bladder wall . NKs, T and B cells are also recruited . The in vitro interaction of bladder cancer cells and BCG or its cell wall skeleton stimulates the maturation of DCs, the major antigen‐presenting cells (APCs) .…”

“…Due to the unique function of the bladder, urine storage, intravesical instillation of drugs is used to treat NMIBC, with BCG intravesical instillation the most successful approach, and the current standard clinical treatment. The mechanisms of BCG‐induced tumour‐specific immunity have been extensively investigated, although many unclear issues remain . Only 25% advanced/metastatic bladder cancers respond to anti‐PD‐1/PD‐L1 ICB , thus further improvement is required.…”