Intravesical anti-PD-1 immune checkpoint inhibition in urothelial bladder cancer in a mouse model.

Abstract

537 Background: Non-muscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with BCG or chemotherapy, but the majority of intermediate- and high-risk cases subsequently recur. Systemic administration of anti-PD-1 immune checkpoint inhibitors (anti-PD-1) are approved treatments for metastatic urothelial bladder cancer. We hypothesized that intravesical instillment with an anti-PD-1 inhibitor would treat localized bladder cancer. Methods: We investigated a syngeneic wild-type mouse model of orthotopic urothelial bladder cancer. We instilled MBT2 cells into wild-type C3H mice to compare treatments, which included weekly intravesical administration of chemotherapy and anti-PD-1 antibody alongside intraperitoneal administration of anti-PD1 antibody. Results: Anti-PD-1 antibody administered by bladder instillment (intravesical route) successfully treats the disease, similarly to anti-PD-1 by systemic route. Anti-PD-1 antibody by either route provides significant survival advantage over isotype control antibody given by bladder instillment. Treatment by immune checkpoint inhibitor increases CD8+ cell infiltration in tumors, particularly when administered intravesically. In addition, antibody treatment avoids toxicity observed for intravesical chemotherapy. Mice who cleared their tumors after initial treatment were rechallenged with tumor engraftment 3-9 months later without any additional treatment, showing initial-anti-PD-1 treated mice did not grow tumors but initial mitomycin-treated mice did grow tumors. Conclusions: Intravesical administration of anti-PD-1 is a promising avenue for treatment of localized bladder cancer, with comparable anti-tumor activity compared to systemic anti-PD-1 in this mouse model.