Login to Access Video or Poster Abstract: MP98-05
Sources of Funding: UroGen Pharma, Ra'anana, Israel

Introduction

Urothelial carcinoma (UC) of the bladder is susceptible to immunotherapy with checkpoint inhibitors, including anti-programmed cell death ligand-1 (anti-PD-L1). However, checkpoint inhibitor treatment has not yet extended to patients with localized UC. We hypothesize that intravesical TMX-101, a bladder formulation of a toll-like receptor-7 agonist that demonstrates efficacy against carcinoma in situ, will enhance the anti-tumor effects of systemic anti-PD-L1 in an orthotopic mouse model of UC.

Methods

We used 32 female C57Bl/6 mice aged 6-8 weeks with MB49 murine UC tumors implanted into the bladder. Treatments (intravesical TMX-101 or vehicle and intraperitoneal anti-PD-L1 or isotype) were given on days 3, 6, and 9 following tumor implantation. Mice were treated with one of four regimens: 1) vehicle + isotype, 2) TMX-101 + isotype, 3) Vehicle + anti-PD-L1, or 4) combination therapy (TMX-101 + anti-PD-L1). Mice were euthanized on day 11. Bladder weight was used as a measure of tumor burden and compared using the Kruskal-Wallis test. Fluorescence activated cell sorting (FACS) analysis of blood, spleen, and regional lymph nodes was performed for T-cell populations._x000D_

Results

Mean bladder weight in mice treated with TMX-101 (34.8±4.7mg), anti-PD-L1 (34.8±3.8mg), and combination TMX-101 and anti-PD-L1 (26.4±3.5mg) was less than in control treated mice (84.8±29.1mg). However, only the combination therapy was statistically significant (p<0.05; Figure 1). As controls, no differences in kidney or spleen weights were found between groups. Histologic analysis confirmed immune cell infiltration in tumors. FACS analysis of blood, spleen, and lymph nodes showed no differences in relative T-cell populations._x000D_

Conclusions

Intravesical TMX-101 and anti-PD-L1 combination therapy significantly reduced tumor burden as demonstrated by bladder weights and histology in an orthotopic mouse model of non-muscle invasive bladder UC.

Funding

UroGen Pharma, Ra'anana, Israel