Abstract 915: Abscopal effect using intratumoral oncolytic virotherapy (LOAd703) is enhanced by anti-PD-1 or anti-PD-L1
Authors: Wenthe Jessica , Naseri Sedigheh , Hellström Ann-Charlotte , Moreno Rafael , Ullenhag Gustav , Alemany Ramon , Lövgren Tanja , Eriksson Emma , Loskog Angelica 
Published: September 2020

Abstract
The purpose of this study was to evaluate the anti-tumor immune response using an oncolytic adenovirus encoding TMZ-CD40L and 4-1BBL (LOAd703) with or without PD-1 or PD-L1 checkpoint blockade. Oncolytic immunostimulatory viruses are currently being evaluated for their capacity to sensitize checkpoint blockade resistant patients to checkpoint blockade therapy since resistance is associated with a non-inflamed tumor phenotype. Herein we evaluated LOAd703, with or without PD-1 or PD-L1 blockade, in preclinical melanoma models. A murine version of LOAd703 (mLOAd703) expressing murine TMZ-CD40L and 4-1BBL was evaluated in the B16-hCD46/C57BL6 model. Immune activation was determined by flow cytometry and multiplex assays from Meso Scale Discovery. Note that adenoviruses do not replicate in murine cells, hence, the treatment effect of mLOAd703 in animal models is only due to expression of the immunostimulatory transgenes. Single and twin-tumor models were used to evaluate the effect of mLOAd703 (1 × 10e9 ffu/treatment) by repeated intravenous (i.v.) or intratumoral (i.t.) injections (one lesion). I.v. treatment did not control tumor growth likely due to the anti-adenovirus antibodies post LOAd703 exposure as evaluated by ELISA. In contrast, i.t. treatment could control growth of the injected tumor as well as hamper growth of the non-injected tumor demonstrating that it is more important to induce systemic immunity from a highly active tumor site (high virus load) than to reach all lesions with a small number of viral particles as shown by PCR. Further, mice with single or twin-tumors were treated with i.t. mLOAd703 (1 × 10e9 ffu), anti-PD-1 or anti- PD-L1 (intraperitoneal 5 mg/kg/injection), or a combination of either antibody and mLOAd703. Anti-PD-1 and PD-L1 monotherapy had only a limited effect on tumor growth in this model, whereas the combination with mLOAd703 could control the growth of the injected tumor and further delay the growth of the non-injected tumor compared to mLOAd703 alone. In agreement, flow cytometry analysis of the tumor biopsies showed an increase of CD8+ T cells in both tumors. In line with tumor inflammation, serum levels of T effector cytokines such as IFNg and TNFa were highest in animals treated with the combination. In conclusion, local mLOAd703 virotherapy induced a systemic anti-tumor immune response in the B16-hCD46 melanoma model. The abscopal effect was further increased by combining mLOAd703 with anti-PD-1 or anti-PD-L1. LOAd703 (i.t.) is currently in clinical development with and without PD-L1.
Citation Format: Jessica Wenthe, Sedigheh Naseri, Ann-Charlotte Hellström, Rafael Moreno, Gustav Ullenhag, Ramon Alemany, Tanja Lövgren, Emma Eriksson, Angelica Loskog. Abscopal effect using intratumoral oncolytic virotherapy (LOAd703) is enhanced by anti-PD-1 or anti-PD-L1 [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 915.