Investig Clin Urol.  2022 Mar;63(2):228-237. 10.4111/icu.20210425.

Immunotherapeutic effects of recombinant Bacillus Calmette–Guérin containing sic gene in ex vivo and in vivo bladder cancer models

• Kim JH
• Choi J
• Kim M
• Kang SJ
• Choi YW
• Choi SY
• Kim SH
• Chang IH

• KMID: 2526897
• DOI: http://doi.org/10.4111/icu.20210425

Abstract

Purpose
The recombinant Bacillus Calmette–Guérin (BCG) containing the streptococcal inhibitor of the complement gene (rBCG-sic) may be more resistant to antimicrobial peptides and improve internalization; therefore, it can enhance the immunotherapeutic effect of the BCG. Here we determined the optimal dose of rBCG-sic and compared its effectiveness with that of BCG.
Materials and Methods
We fabricated a high-throughput 3D-bioprinted bladder cancer-on-a-chip (BCOC) and used it to evaluate the effectiveness of the rBCG-sic in terms of cell viability, cell migration, and cytokine concentrations. Using an orthotopic mouse model, we evaluated its anticancer effect and toxicity via bioluminescence imaging.
Results
T24 cell viability was decreased after treatment with rBCG-sic 30 multiplicities of infection (MOI) versus the same dosage of mock BCG (42.8%±6.4% vs. 75.7%±6.6%, p<0.05). THP-1 cell migration was positively correlated with rBCG-sicconcentration (2.42-fold at 30MOI, p<0.01). The interleukin-6 concentration of rBCG-sic 30MOI was significantly higher than that of mock BCG 30MOI (11.2±1.3 pg/mL vs. 6.7±0.6 pg/mL, p<0.05). In the orthotopic bladder cancer mouse model, lower tumor volume was observed in the rBCG-sic 30MOI group than in the BCG 30MOI group after 10 days of treatment (p<0.05).
Conclusions
We concluded that rBCG-sic is a useful tool for overcoming BCG unresponsiveness in non-muscle invasive bladder cancer. Additionally, high-throughput BCOC with a microfluidic system can successfully reflect the bladder cancer microenvironment.

Keyword

Antimicrobial peptide; Bacillus Calmette–Guérin; Bladder cancer; Genetic recombination