Nonpathogenic Mycobacterium brumae Inhibits Bladder Cancer Growth In Vitro, Ex Vivo, and In Vivo

Abstract

Background: Bacillus Calmette-Guérin (BCG) prevents tumour recurrence and progression in non-muscle-invasive bladder cancer (BC). However, common adverse events occur, including BCG infections.

Objective: To find a mycobacterium with similar or superior antitumour activity to BCG but with greater safety.

Design: In vitro, ex vivo, and in vivo comparisons of the antitumour efficacy of nonpathogenic mycobacteria and BCG.

Intervention: The in vitro antitumour activity of a broad set of mycobacteria was studied in seven different BC cell lines. The most efficacious was selected and its ex vivo capacity to activate immune cells and its in vivo antitumour activity in an orthotopic murine model of BC were investigated.

Outcome measurements and statistical analysis: Growth inhibition of BC cells was the primary outcome measurement. Parametric and nonparametric tests were use to analyse the in vitro results, and a Kaplan-Meier test was applied to measure survival in mycobacteria-treated tumour-bearing mice.

Results and limitations: Mycobacterium brumae is superior to BCG in inhibiting low-grade BC cell growth, and has similar effects to BCG against high-grade cells. M. brumae triggers an indirect antitumour response by activating macrophages and the cytotoxic activity of peripheral blood cells against BC cells. Although no significant differences were observed between BCG and M. brumae treatments in mice, M. brumae treatment prolonged survival in comparison to BCG treatment in tumour-bearing mice. In contrast to BCG, M. brumae does not persist intracellularly or in tumour-bearing mice, so the risk of infection is lower.

Conclusions: Our preclinical data suggest that M. brumae represents a safe and efficacious candidate as a therapeutic agent for non-muscle-invasive BC.

Patient summary: We investigated the antitumour activity of nonpathogenic mycobacteria in in vitro and in vivo models of non-muscle-invasive bladder cancer. We found that Mycobacterium brumae effectively inhibits bladder cancer growth and helps the host immune system to eradicate cancer cells, and is a promising agent for antitumour immunotherapy.

Keywords: Animal models; Bacillus Calmette-Guérin; Cytokines; Immunomodulation; Immunotherapy; Mycobacteria; Urothelial cell line.