Mycobacterium bovis BCG for Bladder Cancer

Bacillus Calmette and Guerin (BCG) is an attenuated strain of Mycobacterium bovis, the pathogen responsible for bovine tuberculosis. Calmette and Guérin cultivated this stable, non-virulent substrain during the development of their tuberculosis vaccine, which was first administered to humans in 1921. As there was no method of preserving viable mycobacterium at that time, BCG required continuous culture. By 1961, the original BCG strain had been serially passaged 1,173 times, resulting in the development of several daughter strains. These strains were then named after the manufacturer and place of origin.

As a result, BCG is not a well-defined pharmacological agent. Rather, it is a term applied to a pool of BCG strains that have acquired phenotypic and genotypic variations due to in vitro culturing in different laboratories under different conditions. These strains can be grouped as shown in Table 1.

Table 1. Groups of BCG substrains

Comparison of substrains

The various substrains have noted differences in immunogenicity, antibiotic susceptibility, and adverse effects. Some studies suggest that these distinctions translate into only small differences in the efficacy of BCG vaccines against tuberculosis. However, head-to-head studies looking at different substrains in bladder cancer are limited. This makes it difficult to compare the clinical efficacy of different strains in this setting.

One study compared the in vitro anti-tumour effects of eight different strains. This study demonstrates that BCG Russia and BCG Connaught are the most effective in inhibiting cell proliferation and inducing cytokine production, while BCG Glaxo was the least effective.

Boehm et al. (2017) conducted a systematic review and meta-analysis to examine whether different BCG strains are associated with different clinical responses in bladder cancer. Their analysis demonstrated that BCG significantly reduced disease recurrence compared to chemotherapy and surgery. However, no BCG strain was found to be significantly superior in preventing disease recurrence.

Supply issues

In recent years, manufacturing issues have led to global shortages of BCG products. Australia currently has a shortage of OncoTICE® (BCG Tice), the Australian-registered BCG product for bladder irrigation. This long-term supply interruption is expected to continue until at least the end of December 2024.

The Therapeutic Goods Administration (TGA) has authorised the supply of an internationally registered alternative under Section 19A of the Therapeutic Goods Act 1989. The alternative product, VesiCulture BCG, is registered in Denmark. The package insert and product labelling is in English.

It is important to appreciate that the strengths of these two products are expressed differently. An OncoTICE vial contains 2-8 × 10⁸ colony-forming units (CFU), which may also be expressed as 500 million CFU. In contrast, the strength of VesiCulture is typically stated as 30mg per vial but may also be referred to as 2.5 x 10⁸ CFU.

In clinical trials, a standard dose is often defined as 120mg for the Danish strain and 5 × 10⁸ CFU for the TICE strain. This equates to four vials of VesiCulture or one vial of OncoTICE.

Some of the other key differences between VesiCulture and OncoTICE® are summarised in Table 2.

Table 2. Comparison of OncoTICE and VesiCulture (adapted from Link Communication 2023)

BCG Efficacy

The anti-tumour activity of BCG is thought to be related to local modulation of immune responses, leading to inflammation and the subsequent elimination of malignant cells. Interaction of BCG with urothelial cells may result in immunological effects, such as the induction of chemokines (e.g. interleukin-8), pro-inflammatory cytokines (e.g. granulocyte-macrophage colony-stimulating factor, tumour necrosis factor α, interleukin-6), and the upregulation of adhesion-molecule expression.

There are a number of conditions that should be met to improve the likelihood of treatment success with BCG. These include:

• The patient must be immunocompetent to ensure a robust immune response;
• The tumour burden should be small;
• BCG must come into direct contact with the tumour; and
• The dose must be adequate to stimulate an immune reaction.

The current evidence suggests that the use of an established BCG strain from another country does not disadvantage patients with bladder cancer. However, healthcare professionals are advised to take additional care when dispensing and administering any product that they are not familiar with.

Further information:

• OncoTICE – consult the Australian-approved product information;
• VesiCulture – consult the Instructions for Use; and
• Australia and New Zealand Urological Nurses Society publishes guidelines on Intra-vesical therapy for Non-Muscle Invasive Bladder Cancer (NMIBC).