Intravesical High Dose BCG Tokyo and Low Dose BCG Tokyo with GMCSF+IFN α Induce Systemic Immunity in a Murine Orthotopic Bladder Cancer Model

Abstract

This study evaluates a short therapy schedule for bladder cancer using BCG Tokyo. BCG Tokyo was evaluated in vitro using bone marrow derived dendritic cells, neutrophils, RAW macrophages and the murine bladder cancer cell line, MB49PSA, and compared to other BCG strains. BCG Tokyo > BCG TICE at inducing cytokine production. In vivo, high dose (1 × 107 colony forming units (cfu)) and low dose (1 × 106 cfu) BCG Tokyo with and without cytokine genes (GMCSF + IFNα) were evaluated in C57BL/6J mice (n = 12–16 per group) with orthotopically implanted MB49PSA cells. Mice were treated with four instillations of cytokine gene therapy and BCG therapy. Both high dose BCG alone and low dose BCG combined with cytokine gene therapy were similarly effective. In the second part the responsive groups, mice (n = 27) were monitored by urinary PSA analysis for a further 7 weeks after therapy cessation. More mice were cured at day 84 than at day 42 confirming activation of the immune system. Cured mice resisted the re-challenge with subcutaneous tumors unlike naïve, age matched mice. Antigen specific T cells recognizing BCG, HY and PSA were identified. Thus, fewer intravesical instillations, with high dose BCG Tokyo or low dose BCG Tokyo with GMCSF + IFNα gene therapy, can induce effective systemic immunity.

BCG infection dose guides dendritic cell migration and T cell priming in the draining lymph node

“…In animal models of bladder cancer, the protective effects of BCG Tokyo were observed at 10 7 CFUs. Similar protective effects were achieved with a lower dose of 10 6 CFUs when given together with GM‐CSF and IFN‐α 25 …”

“…Similar protective effects were achieved with a lower dose of 10 6 CFUs when given together with GM-CSF and IFN-α. 25 Notwithstanding differences in patient age and vaccine strain, clinical dose of BCG is brutally higher for bladder cancer than for TB; an equivalent of approximately 1-8 × 10 8 CFUs of BCG TICE is normally instilled in the urethra, 26 while the recommended clinical dose for TB vaccination with BCG SSI 1331 is 1-4 × 10 5 CFUs for neonates and 2-8 × 10 5 CFUs for adults. 4 The equivalent of the more commonly administered TB vaccination dose would be approximately 3000 CFUs in mice if based on human infant body weight.…”