Preclinical study of safety and efficacy in vivo of a yttrium-90 resin microspheres glue formulation in a large animal model of pancreatic cancer.

e16438 Background: Pancreatic ductal adenocarcinoma (PDAC), the most common cancer type in the pancreas, constitutes a major health problem worldwide because of its poor prognosis with a five-year relative survival rate of 12%. Methods: BetaGlue Therapeutics has developed an implantable medical device called YntraDose consisting of a β-emitting yttrium-90 radioisotope coated resin microspheres embedded in a polymerizing biocompatible glue matrix. This device will be developed as a neoadjuvant therapy option in combination with chemotherapy as a first-line treatment option for patients with locally-advanced PDAC (LA-PDAC). . To that end, a novel orthotopic animal model of pancreas cancer was created in a transgenic pig (called “oncopig”) whereby porcine KRAS and TP53 cDNA were cloned before site-directed mutagenesis was performed to introduce the oncogenic G12D and R167H mutations, respectively. The two cDNAs were then introduced into an adenoviralvector containing a CAG promoter followed by a Lox-Stop-Lox (LSL) sequence which prevents expression of the transgenes until it is removed by Cre recombinase followed by a single copy of the KRASG12D and TP53R167H. The expression of P53R167H and KRASG12D proteins induces the tumor. Adenovirus expressing Cre recombinase (AdCre) injections were performed in the porcine pancreas and after 2 weeks the tumor reached a size ranging from 2 to 3 cm in the longest diameter. . A 2.71ml mean volume of YntraDose corresponding to an activity ranging from 10.1 to 11.9 MBq was injected percutaneously under laparoscopic guidance in each of the 5 treated animals. All the study animals underwent positron emission tomography (PET)-CT imaging 1 day post-procedure and then again weekly before being sacrificed 1 month post-treatment. Results: All animals remained alive for the full study period of 30 days with no reported serious adverse events. The mean delivered dose of yttrium-90 was 54Gy (range 49-72 Gy) . No leakage of YntraDose was detected beyond the site of administration adjacent and distant organs such as the stomach, duodenum and lungs as demonstrated on the PET-CT scan that was performed 1-hour post-procedure. Follow-up PET-CT images revealed excellent yttrium-90 deposition within the tumor with a “surgical” margin beyond the tumor. After 1 month, visual necroscopy assessment showed evidence of necrosis but also indicated tumor debulking at the YntraDose implantation site. Conclusions: Based on these preliminary findings, percutaneous intratumoral administration of YntraDose in an orthotopic animal model of pancreatic cancer was safe and feasible thereby indicating the potential therapeutic advantage of this approach to treat pancreatic cancer.