Abstract LB024: Permeation enhancer is necessary for the optimized PRV131 mediated cisplatin intratumoral delivery

Abstract

Abstract PRV131 is an effective and safe polymeric nanoparticle suspension for intratumoral cisplatin delivery. Background: Systemic administration of platinum-based chemotherapy often leads to dose-limiting toxicity, affecting quality of life. While intratumoral delivery may reduce or eliminate the systemic toxicities and adverse side effects associated with intravenous cisplatin chemotherapy, this approach is not commonly adopted, in part due to the difficulty to obtain high drug retention in the tumor and control sustained drug release. PRV131 is a highly-concentrated cisplatin polymeric nanoparticle suspension carefully designed for intratumoral administration. The goal of this study was to assess the safety and efficacy of PRV131 as a monotherapy and in combination with a checkpoint inhibitor in a well-established preclinical murine colorectal adenocarcinoma model. Experimental Methods: MC38 cells were inoculated subcutaneously into the flanks of C57BL/6J female mice and allowed to grow to an average size of 100 mm3. Mice were then randomized into 6 groups of n=10: control (saline injection), 100 µg of cisplatin solution, 400 µg of cisplatin solution, 400 µg of PRV131, 400 µg of PRV131 + 200 µg systemic anti-PD1, and 200 µg systemic anti-PD1. A single injection of PRV131 or cisplatin solution was administered directly into the tumor on Day 1. Intraperitoneal anti-PD-1 was administered on Day 1 and Day 10. Mice were then monitored for efficacy (tumor measurements) and safety (overall health, weight loss and mortality). The durability of a single PRV131 injection was also studied. Efficacy and safety were adjudicated at 28 days post treatment and treatment durability assessment extended through 60 days post inoculation. Results: Our data demonstrates that PRV131 400 µg was significantly more effective than cisplatin solution at an equivalent dose. 80% of PRV131 treated mice survived to day 60 post inoculation, and no detectable tumor was found in 60% of PRV131 treated mice 38 days post administration. The safety profile was acceptable, with no mouse lost more than 20% body weight. Notably, efficacy profile of PRV131 monotherapy did not differ substantially from the addition of anti-PD-1 to the treatment, suggesting a high translational relevance of our drug delivery platform. Conclusion: A single intratumoral injection of PRV131 is well-tolerated in C57BL/6J female mice and elicits a durable antitumor response that lasts for over 30 days, laying the groundwork for its incorporation in clinical trial setting. Citation Format: Manijeh Goldberg, Aaron Manzi, Stefanie Cantin, Peter Conway, Jonathan Shikora, Adelaide McFarland, Matt Cayer, Lillyanna Dunn, Courtney Ball, Alexander T. Pearson, Ari J. Rosenberg, Nishant Agrawal, Evgeny Izumchenko. Permeation enhancer is necessary for the optimized PRV131 mediated cisplatin intratumoral delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB024.