Mycobacterium Cell Wall: An Alternative to Intravesical Bacillus Calmette Guerin (BCG) Therapy in Orthotopic Murine Bladder Cancer

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Abstract
The antitumor effect of intravesical mycobacterium cell wall (MCW) therapy on orthotopic and heterotopic bladder tumors in the mouse was assessed with magnetic resonance imaging (MRI). The live bacillus Calmette Guerin (BCG) organism was replaced with a cell wall extract derived from the outer capsule of Mycobacterium phlei. This alternative form of intravesical therapy was used with the aim of reducing the toxicity associated with the live mycobacterium organism without compromising efficacy. Response to multiple doses of intravesical MCW and BCG was assessed in mice with established MBT-2 tumors after transurethral tumor implantation. Serial MRI of BCG-treated mice revealed significant tumor regression. The MR images correlated well with the corresponding histology of the whole mount bladder sections. Treatment with MCW also resulted in significant inhibition of tumor growth compared with control untreated animals (p < 0.05) although the antitumor effect was less pronounced than that of live BCG. Treatment was well tolerated in the MCW group with no apparent ill effects. Flow cytometric (FCM) analysis of bladder washings with phenotype-specific monoclonal antibodies revealed predominantly a CD3+ T cell infiltrate in the control and BCG-treated as well as the MCW-treated mice. The CD4+ (helper/inducer) subset of T cells predominated over the CD8+ (suppressor/cytotoxic) subset in both the BCG- and MCW-treated animals, and the CD4+/CD8+ ratio in both of the treated groups differed significantly from that of the control untreated groups. Intravesical MCW appears to invoke a similar inflammatory response in the mouse bladder mucosa as the live BCG organism and retains an antitumor action. It deserves further evaluation as a potential antitumor agent against bladder cancer. A Phase II clinical trial is now underway.