Abstract 6535: A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties

Abstract

Abstract Oncolytic viruses offer the potential to be transformative in the treatment of cancers through their ability to selectively infect, replicate in and kill tumors whilst able to potently activate the immune system. Their activity can be further augmented through the addition of transgenes leading to tumor selective gene expression. Our proprietary Newcastle Disease virus (NDV) backbone has previously been demonstrated to have broad oncolytic activity whilst inducing potent anti tumor immune effects in preclinical models. We set out to test whether the incorporation of an IL-12 transgene into the NDV backbone could result in transgene dependent enhancement in anti tumor efficacy. In vitro, the addition of IL-12 into the NDV genome did not alter NDV infectivity in tumor or non-cancer cells compared to the backbone virus and infection of cancer cells resulted in the production of bioactive IL-12. In an immune-deficient xenograft model, a single systemic administration of NDVhuIL-12 resulted in tumor selective replication and local IL-12 production within the tumor microenvironment (TME). In syngeneic tumor models, local tumoral administration of NDVmuIL-12 resulted in the generation of an elevated and more durable type II interferon response compared to NDV-GMCSF; though similar pharmacokinetic profiles were observed. This difference in cytokine response correlated with superior single agent efficacy of NDVmuIL-12 compared to NDV alone in the B16F10 model. Furthermore, NDVmuIL-12 demonstrated anti tumor efficacy in several NDV refractory models, suggesting tumor expression of IL-12 was necessary to drive anti tumor activity in some circumstances. Across all models tested significant changes in the tumor immune microenvironment, previously associated with enhanced anti tumor immunity were observed in NDVmuIL-12 tumours compared to backbone virus alone. There is an abundance of pre-clinical data demonstrating that IL-12 can exert potent anti tumor activity, but its clinical application has been hindered through its toxicity when administered systemically. These data provide evidence that recombinant NDV could be utilised to deliver IL-12 to the TME when administered systemically and that the addition of IL-12 potentiates the anti tumor activity of NDV. Citation Format: James Harper, Andrew Leinster, Nicola Rath, Shannon Burke, Kathy Mulgrew, Hong Jin, Robert W. Wilkinson. A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6535.