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

Abstract

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.

Antitumor Effect and Induced Immune Response Following Exposure of Hexaminolevulinate and Blue Light in Combination with Checkpoint Inhibitor in an Orthotopic Model of Rat Bladder Cancer

“…Local immunotherapy administration into the bladder could represent a substantial clinical benefit, reducing systemic exposure and side effects. Our study in rats and the study reported by Kirschner et al [38] in mice are encouraging in this respect. However, additional clinical trials are warranted before intravesical instillation of anti-PD-L1 could be widely used in humans alone or in combination with HAL and BL.…”

“…A recent study of Kirschner et al compared efficacy of intravesical versus systemic (intraperitoneal) administration of an anti-PD-1 inhibitor in the treatment of localized bladder cancer in an orthotopic mouse model [38]. Intravesical anti-PD-1 administration had trend to improved survival thus providing effective anti-tumor treatment for bladder tumors.…”

Intravesical oncolytic virotherapy and immunotherapy for non‐muscle‐invasive bladder cancer mouse model

“…In our previous study, six once-weekly administrations of intravesical anti-PD-1 treatment had a very high rate of clearing bladder tumours (nearly 100% in most cohorts) [6].…”

“…In our previous study, six once‐weekly administrations of intravesical anti‐PD‐1 treatment had a very high rate of clearing bladder tumours (nearly 100% in most cohorts) [6]. In the present study, we tested if only one intravesical instillation of anti‐PD‐1 treatment and/or reovirus would be sufficient to treat bladder tumours.…”

B2B: Bladder Cancer Summary

“…In addition, a novel approach for ICI therapy was recently presented. In SUBDUE-1, a dose-finding phase 1b trial, intravesical injection of durvalumab is under investigation for patients with NMIBC [39], an approach that has shown promising results in the pre-clinical studies [40].…”