Intravesical Anti-PD-1 Immune Checkpoint Inhibition Treats Urothelial Bladder Cancer in a Mouse Model.

PURPOSE

Nonmuscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with bacillus Calmette-Guérin or chemotherapy. For bacillus Calmette-Guérin-refractory disease, systemic anti-PD-1 (programmed cell death protein 1) immune checkpoint inhibition is a treatment. Our aim is to test whether intravesical instillment with anti-PD-1 inhibitor treats localized bladder cancer as effectively as systemic administration.

MATERIALS AND METHODS

We investigated an orthotopic mouse model of urothelial bladder cancer using MBT2 cells instilled into the bladders of syngeneic, wild-type C3H mice. Groups of 10 mice received each treatment for comparison of intravesical anti-PD-1, intraperitoneal anti-PD1, and intravesical chemotherapy. The primary outcome was overall survival and secondary outcomes included long-term immunity and toxicity.

RESULTS

Anti-PD-1 administered by bladder instillment (intravesical route) successfully treats localized bladder cancer and has similar overall survival to anti-PD-1 by systemic route. Anti-PD-1 by either route provides a significant survival advantage over control antibody. Anti-PD-1 increases CD8+ cell infiltration in tumors, particularly when administered intravesically. 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. Initial anti-PD-1-treated mice did not grow tumors when rechallenged, which suggests long-term immunity exists, but initial mitomycin-treated mice readily grew tumors indicating no immunity occurred by chemotherapy treatment.

CONCLUSIONS

Intravesical administration of anti-PD-1 is a promising treatment route for localized bladder cancer, with comparable overall survival to systemic anti-PD-1 in this mouse model. Intravesical anti-PD-1 increases CD8+ T cells in treated tumors and long-term immunity was seen to tumor rechallenge.