Intravesical Mycobacterium brumae triggers both local and systemic immunotherapeutic responses against bladder cancer in mice

Abstract

The standard treatment for high-risk non-muscle invasive bladder cancer (BC) is the intravesical administration of live Mycobacterium bovis BCG. Previous studies suggest improving this therapy by implementing non-pathogenic mycobacteria, such as Mycobacterium brumae, and/or different vehicles for mycobacteria delivery, such as an olive oil (OO)-in-water emulsion. While it has been established that BCG treatment activates the immune system, the immune effects of altering the mycobacterium and/or the preparation remain unknown. In an orthotopic murine BC model, local immune responses were assessed by measuring immune cells into the bladder and macromolecules in the urine by flow cytometry and multiplexing, respectively. Systemic immune responses were analyzed by quantifying sera anti-mycobacteria antibody levels and recall responses of ex vivo splenocytes cultured with mycobacteria antigens. In both BCG- and M. brumae-treated mice, T, NK, and NKT cell infiltration in the bladder was significantly increased. Notably, T cell infiltration was enhanced in OO-in-water emulsified mycobacteria-treated mice, and urine IL-6 and KC concentrations were elevated. Furthermore, mycobacteria treatment augmented IgG antibody production and splenocyte proliferation, especially in mice receiving OO-in-water emulsified mycobacteria. Our data demonstrate that intravesical mycobacterial treatment triggers local and systemic immune responses, which are most significant when OO-in-water emulsified mycobacteria are used.

Mycolicibacterium brumae is a Safe and Non-Toxic Immunomodulatory Agent for Cancer Treatment

“…Among them, M. brumae has been described as a potential immunotherapeutic agent for NMIBC treatment. M. brumae shares the anti-tumor ability of BCG, as well as its capacity to trigger an immune response during intravesical instillations [5,24,25,32]. In contrast to BCG, no CFU have been isolated in M. brumae-treated tumor bearing mice [24,25], but a systematic safety and toxicity study on M. brumae needs to be performed.…”

<p>Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer: An Update</p>

“…68,69 Among nontuberculous mycobacteria, M. brumae has recently shown in preclinical studies a potential role in NMIBC since it inhibits tumor proliferation and triggers a proper antitumor immune response. [70][71][72] One important issue of mycobacterial delivery remains their hydrophobicity and, consequently, clump formations. Hence, an optimized emulsion has been recently published to decrease clump formation, which leads to increased antitumor activity triggered by BCG and M. brumae.…”

Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers

“…No cases of infections due to M. brumae have been described, and its non-pathogenicity and non-toxicity have recently been demonstrated [36,37]. M. brumae has shown to inhibit tumor growth and increase survival in preclinical studies for bladder cancer (BC) treatment [38][39][40][41][42]. Finally, MTBVAC, a Spanish vaccine developed by deleting virulence factors of M. tuberculosis and currently in clinical trials for TB prevention [43], has been analyzed for its value in BC treatment [44].…”

“…Cancers 2020, 12, x 3 of 25 treatment [38][39][40][41][42]. Finally, MTBVAC, a Spanish vaccine developed by deleting virulence factors of M. tuberculosis and currently in clinical trials for TB prevention [43], has been analyzed for its value in BC treatment [44].…”