Brigham & Women's Hospital, Harvard Medical School
Introduction: Immune checkpoint blockade (ICB) produces a durable response in only 20% of patients with bladder cancer and adjuncts are needed to render this treatment more robust. We sought to determine the synergistic effects of PI3K inhibition and ICB when utilized in combination for the treatment of bladder cancer using a mouse model. Methods: Human and mouse bladder cancer cell lines were utilized for in vitro tests of a previously-established PI3K inhibitor, copanlisib. These cells lines were subsequently injected subcutaneously into laboratory mice to determine in vivo activity and the anti-tumor mechanisms of action of PI3K inhibition, ICB (achieved with anti-PD-1 therapy), and synergistic therapy between the two. Results: PI3K inhibition with copanlisib showed a dose-dependent suppression of cell growth in T24 (human bladder cancer cell line) and UPPL (mouse bladder cancer cell line) (Figure 1). Mouse bladder cancer models were generated by subcutaneously implanting UPPL cells in transgenic mice. Compared to the treatments with copanlisib and anti-PD-1 therapy alone, which only slightly delayed tumor growth, the combination treatment significantly delayed tumor growth in these models (Figure 2a). For injected mice, the median survivals of the of the control, copanlisib, and combination groups were 48, 37, and 65 days, respectively (Figure 2b). Tumor volume in the combination group was the smallest when compared with the control group (p < 0.001), copanlisib (p = 0.001), and anti-PD-1 (p < 0.001) monotherapy (Figure 2c). Conclusions: Combination PI3K inhibition and ICB functions synergistically to promote a pro-inflammatory tumor reaction and has significant anti-tumor effects in bladder cancer. This regimen serves as an enticing possibility to render immunotherapy treatment in bladder cancer more robust, and warrants further investigation for safety and efficacy in human clinical trials. SOURCE OF Funding: U54 Grant, R01 Grant, VA Merit Review Grant.
