Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ-producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients' response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses.
Intravesical Bacillus Calmette Guérin (BCG) immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1) duration between resection and the first instillation; (2) BCG dose; (3) indwelling time; and (4) treatment interval of induction therapy – using cure rate as the primary endpoint. Based on available clinical and in vitro experimental data, we constructed and parameterized a stochastic mathematical model describing the interactions between BCG, the immune system, the bladder mucosa and tumor cells. The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy.
Introduction: Forty years ago Zbar and colleagues demonstrated that bacillus calmette guérin (BCG) is capable of provoking an immune response against experimentally induced tumors. The conditions for successful tumor immunity were defined by a i) limited number of tumor cells in ii) close contact with a iii) sufficient number of bacteria and iv) the ability of the organism to mount a BCG specific immune response. These findings led to the development of what is currently the standard of care for the treatment of patients with non-muscle invasive bladder cancer. Whether the genetic drift between BCG strains that are routinely used in treatment protocols for bladder cancer affects the generation of successful tumor immunity is unknown. Here we compared two of the commonly used BCG strains (Connaught and Tice) in the treatment of bladder cancer in an animal model. Methods: Naïve or bladder cancer bearing (orthotopic implantation of syngeneic MB49 cells) Bl/6 mice received either a single s.c. injection or weekly intravesical instillation of 107 CFUs of BCG Tice or Connaught. Twelve days after the 4th intravesical treatment or after the single s.c. immunization, the bladders, spleens and draining lymph nodes (DLN) were removed, enzymatically digested and the resulting cell suspensions analyzed by flow cytometry, including assessment of BCG specific CD8+ T-cells. Lymph node extracts were cultivated for the enumeration of BCG CFUs. Tumor bearing animals were assessed for their overall survival. Results: In non-tumor bearing animals, BCG Connaught lead to a more robust influx of adaptive immune cells into the bladder and primed significantly more BCG specific cytotoxic CD8+ T-cells. Compared to BCG Connaught, BCG Tice was less capable to disseminate into the draining lymph nodes (DLN), and induced less Th1 polarized CD4+ T-cells in the bladder, DLN and spleens, as assed by intracellular T-bet staining. These findings were independent of BCG preparation (clinical grade versus laboratory grade) and were seen for identical treatment doses. Finally, mice, orthotopically challenged with MB49 bladder cancer cells, showed significantly better survival if treated with BCG Connaught as compared to BCG Tice. Conclusion: Here we show that different BCG strains significantly impact the immunological response of adaptive immunity. Along with a stronger Th1 immune response, favoring the generation of cytotoxic T-cells, BCG Connaught improves survival as compared to BCG Tice in vivo. These findings implicate potential consequences for clinical practice and corroborate testing of different BCG strains in prospective clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5386. doi:1538-7445.AM2012-5386
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