The Oncopig bladder cancer model, an innovative large animal platform for evaluating treatment effects.

857 Background: Bladder cancer carries a high recurrence rate despite availability of several treatment options including surgery, chemotherapy, radiation, and immunotherapy, resulting in the highest cost of lifelong treatment per patient and highlighting the need for development of novel diagnostic and therapeutic strategies. Unfortunately, results from current bladder cancer models do not effectively translate to clinical practice (mouse models) or are rare and not inducible (canine models). This, in addition to the use of endoscope-based approaches for bladder cancer treatment highlights the critical need for large animal bladder cancer models to improve patient outcomes. Pigs represent an ideal platform that provide both regulatory acceptable and clinically relevant large animal cancer models due to their similar physiology, size, genetics, immunity, and metabolism in relation to humans. The Oncopig bladder cancer model is an ideal tool for testing endoscopic and other oncolytic-based treatments. Methods: The Oncopig cancer model develops tumors following induced expression of KRAS G12D and TP53 R167H driver mutations utilizing an adenoviral vector encoding Cre recombinase (AdCre). Two procedures for cystoscope-based AdCre delivery were evaluated. In procedure I (Proc-I) a combination of AdCre and N-Dodedcyl-beta-maltoside, a sugar-like surfactant utilized to dissolve the glycoaminoglycans layer, was instilled into the bladder (1h; n=3). In procedure-II (Proc-II) the bladder urothelium was superficial denuded at 3 sites and subsequent AdCre was instilled into the bladder (1h; n=4). Oncopigs underwent CT scans and follow-up cystoscopy, and were euthanized at 3 timepoints (day 14, 21, and 28) to assess temporal bladder tumor growth. Tumor samples were collected at necropsy for histopathological evaluation (H&E, TP53, Ck34be12, vimentin, and CD3) and to evaluate tumor stage. Results: In total 6/7 Oncopigs developed endoluminal tumors. Tumor-induction efficacy was 100% for Proc-I (n=3/3) and 75% for Proc-II (n=3/4). Two tumor types were observed: urothelial cell carcinomas of sarcomatoid variant (Proc-I: n=3/3; Proc-II: n=2/4) and inflammatory tumors (Proc-II: n=1/4). After 14 days, pT1 tumors were observed for Proc-I, while pT2 tumors were observed for Proc-II. After 21 days, both pT1 and pT2 tumors were observed for Proc-I, while Proc-II tumors remained pT2. Conclusions: The Oncopig bladder cancer model can develop both superficial and muscle invasive urothelial cell carcinomas with sarcomatoid variant. Tumors develop rapidly (within 2 weeks), with tumor invasiveness correlated with time post tumor induction and procedure used, making this an ideal model for evaluation of novel therapeutic approaches. Further exploration and development of additional tumor models including further translational characterization will be important for broader utility.