Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy

Rentsch, Cyrill Achim; Birkhäuser, Frédéric; Biot, Claire; Gsponer, Joël R; Bisiaux, Aurélie; Wetterauer, Christian; Lagranderie, Micheline; Marchal, Gilles; Orgeur, Mickael; Bouchier, Christiane; Bachmann, Alexander; Ingersoll, Molly A; Brosch, Roland; Albert, Matthew L; Thalmann, George (2014). Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. European urology, 66(4), pp. 677-688. Elsevier 10.1016/j.eururo.2014.02.061

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BACKGROUND

Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown.

OBJECTIVES

To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice.

DESIGN, SETTING, AND PARTICIPANTS

A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice.

INTERVENTION

Patients were randomized to receive six instillations of BCG Connaught or Tice. For experimental studies, BCG strains were compared in C57Bl/6 mice. Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG. BCG genomic DNA was sequenced and compared with reference genomes.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

Recurrence-free survival was the primary end point of the clinical study. The Kaplan-Meier estimator was used for estimating survival and time-to-event end points. Nonparametric tests served for the analysis of the in vivo results.

RESULTS AND LIMITATIONS

Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice (p=0.0108). Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group (p=0.09). In mice, BCG Connaught induced stronger T-helper cell 1-biased responses, greater priming of BCG-specific CD8(+) T cells, and more robust T-cell recruitment to the bladder than BCG Tice. Genome sequencing of the BCG strains revealed candidate genes potentially involved in the differential clinical responses.

CONCLUSIONS

BCG strain may have an impact on treatment outcome in NMIBC immunotherapy.

PATIENT SUMMARY

We compared the efficacy of two commonly used bacillus Calmette-Guérin (BCG) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught. We also identified genetic differences that may explain the differential efficacy of the Connaught and Tice BCG strains.

TRIAL REGISTRATION

NCT00003779.

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