Genetically Regulated Response to Intravesical Bacillus Calmette Guerin Immunotherapy of Orthotopic Murine Bladder Tumor

Abstract

Purpose Genetically regulated host response to intravesical Bacillus Calmette Guerin (BCG) immunotherapy was assessed using the murine bladder tumor MM45T in Bcg r and Bcg s inbred congenic strains of mice. Materials and Methods Tumor detection and monitoring of treatment response to BCG was carried out using magnetic resonance imaging (MRI) of BALB/c (Bcg s allele) and BALB/c. CD2 (CD2) (Bcg r allele) mice implanted orthotopically with MM45T tumor cells. Intravesical BCG instillation (3 doses per week for 3 weeks) was used as prophylaxis against tumor implantation in both Bcg r and Bcg s strains and as definitive treatment against MRI-confirmed established tumors. Tumors implanted in both strains of untreated mice served as controls. Intravesical injection of BCG was also performed in established heterotopic subcutaneous tumors in both strains. Immunologic response in all groups was assessed by flow cytometric analysis of the bladder irrigation fluid cell composition, measuring CD4 sup + (helper/inducer) and CD8 sup + (cytotoxic/suppressor) cell subsets. Results Intralesional injection of BCG into established heterotopic tumors showed growth inhibition in the Bcg s strain but not in the Bcg sup r strain. Intravesical BCG treatment against established orthotopic tumors showed significant tumor regression in the Bcg s strain compared to control but there was no effect in the Bcg r strain. Conclusion The differential anti-tumor activity of BCG in the Bcg s and Bcg r congenic murine strains supports the notion that Bcg gene-controlled responsiveness to BCG innoculation determines, at least partially, the host response to immunotherapy. These results have potential clinical significance in patient selection for intravesical therapy for bladder cancer.