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.
Highlights
High risk non-muscle invasive bladder cancer (NMIBC) is characterized by frequent recurrence
A comparison was made of the three strains on murine DC and neutrophils at a multiplicity of infection (MOI) of one cell to five bacteria (1:5) [36]
In the orthotopic murine model, low dose BCG Tokyo alone and high dose BCG when combined with GMCSF and IFNα therapy were not successful as an immunotherapeutic agent on a short therapy course of four instillations
Summary
High risk non-muscle invasive bladder cancer (NMIBC) is characterized by frequent recurrence. Today’s strains have some genetic losses, which correlate with different immunostimulatory capacity [2], cytokine production and cytotoxicity on human bladder cancer cell lines and immune cells [3,4]. BCG Connaught, Glaxo, Moreau, RIVM, Pasteur, Tice and Tokyo have been used clinically but few comparison trials have been satisfactorily completed [5]. BCG Tokyo was reported to be as efficacious as BCG Connaught in a clinical trial that was not completed due to the worldwide shortage of BCG Connaught [6]. It is believed that the cytokines both recruit and activate immune cells [9].
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