BCG-Mediated Bladder Cancer Immunotherapy: Identifying Determinants of Treatment Response Using a Calibrated Mathematical Model

Abstract

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.

The Dose-Response Relationship of bacillus Calmette-Guérin and Urothelial Carcinoma Cell Biology

“…22 Finally, a mathematical model based upon clinical and basic research findings found a positive correlation of BCG dose with treatment response. 23 Against a backdrop of potential clinical relevance and suggestive basic research this study was designed to determine the effect of BCG dose on a number of intermediate tumor response endpoints that characterize the direct effect of BCG on UC cell biology. Our experiments confirmed earlier reports of the dose/time relationship of BCG adherence/ internalization to UC cells.…”

From concept to clinic: mathematically informed immunotherapy

“…To minimize these risks, a stability condition for the tumor-free state may be defined by upper and lower bounds for the average dose per unit time [102]. BCG is also typically used in an adjuvant capacity post-resection; shortening the time between surgery and the first BCG instillation may be beneficial to patient outcome, as may extending the indwelling time beyond the current standard of care [103]. Furthermore, despite initial computational evidence to the contrary [101,102], patient response may also improve significantly under the combination of both BCG and IL-2 infusion [104].…”

Summary of the 8th Annual Bladder Cancer Think Tank: Collaborating to move research forward

“…Lastly, Dr. Albert presented results from his laboratory’s exploration of how a patient’s immune system responds to Bacille Calmette-Guérin (BCG) treatment for NMIBC [48,49]. Examining how the immune system responds to BCG therapy has defined strategies that may help improve response rates in patients with bladder cancer, and perhaps permit extension of this successful immunotherapeutic strategy to other malignancies.…”