Anti‐interleukin‐10 R 1 monoclonal antibody in combination with bacillus Calmette–Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti‐tumour immunity

Summary Effective treatment of bladder cancer with bacillus C almette– G uérin ( BCG ) depends on the induction of a T helper type ( T h) 1 immune response. Interleukin ( IL )‐10 down‐regulates the T h1 response and is associated with BCG failure. In this study, we investigated whether blocking IL ‐10 signalling could enhance the BCG ‐induced Th1 response and anti‐tumour immunity in a murine orthotopic tumour model. Treatment with BCG and anti‐ IL ‐10 receptor 1 monoclonal antibody (anti‐ IL ‐10 R 1 m A b) increased the interferon ( IFN )‐γ to IL ‐10 ratio in both splenocyte cultures and urine. Mice bearing luciferase‐expressing MB 49 ( MB 49‐ L uc) tumours were treated and followed for tumour growth by bioluminescent imaging, bladder weight and histology. Mice treated with phosphate‐buffered saline ( PBS ) (group 1), BCG plus control immunoglobulin ( I g) G 1 (group 2) or BCG plus anti‐ IL ‐10 R 1 m A b (group 3) showed 0, 6 and 22% tumour regression, respectively. The mean bladder weight of group 3 mice was substantially lower than those of groups 1 and 2 mice. Remarkably, 36% of group 1 and 53% of group 2 mice but no group 3 mice developed lung metastasis ( P  = 0·02). To investigate the mechanisms underlying the effect of combination therapy, splenocytes were stimulated with S12 peptide (serine mutation at codon 12 of the K ‐ ras oncogene) known to be expressed in MB 49‐ L uc cells. Induction of ras mutation‐specific IFN ‐γ and cytotoxicity was observed in mice treated with combination therapy. These observations indicate that BCG, in combination with anti‐ IL ‐10 R 1 m A b, induces enhanced anti‐tumour immunity that is protective against lung metastasis. Anti‐ IL ‐10 R 1 m A b demonstrates systemic effects and may prove useful in clinical practice for treating bladder cancer in high‐risk patients.