Abstract 4979: Ofranergene Obadenovec (VB-111), an anti-cancer gene therapy, induces immunologic responses in solid tumors transforming cold tumors to hot tumors
Authors: Shapira-Frommer Ronnie , Minei Tamar Rachmilewitz , Barshack Iris , Mendel Itzhak , Yakov Niva , Cohen Yael C. , Breitbart Eyal , Harats Dror , Penson Richard T. 
Published: August 2019

Abstract
Introduction: Ofranergene Obadenovec (VB-111) is a non-replicating adenovirus 5 (Ad-5, El-deleted) carrying a proapoptotic human Fas-chimera transgene that targets angiogenic blood vessels and leads to vascular disruption. Improved responses seen among patients experiencing post treatment fever suggest that VB-111’s mode of action involves induction of a tumor directed immune response. The following experiments were conducted to assess if VB-111 may alter the immunogenic profile of the tumor.
Methods: Biopsies were obtained from 3 patients with recurrent platinum-resistant ovarian cancer treated with intravenous VB-111 1x1013 viral particles (VPs) every 2 months in combination with weekly paclitaxel. H&E and Immunohistochemistry (IHC) were performed for CD8 and CD4 intratumoral T-cells, and results were compared to pre-treatment specimens and to untreated controls. In parallel, in the Lewis Lung Carcinoma (LLC) model, mice were randomly treated with intravenous saline or VB-111 at doses of 1x109 or 1x1011 VPs. Upon sacrifice lungs were harvested and weighted. Tumor burden was assessed, and Immunohistochemistry with anti-CD8 antibody for the presence of infiltrating cytotoxic T-cells was performed.
Results: Specimens from Ovarian Cancer taken before treatment with VB-111 showed no or minimal T-cell infiltration. One month after VB-111 treatment, metastatic lesions demonstrated increase in CD8 (up to 74 CD8+ cells/HPF) and CD4 tumor infiltrating T-cells. At 4.5 months following first drug administration (post 3rd dose) a liver lesion showed necrotic and fibrotic tissue with no viable tumor, lymphocytic aggregate, intensive staining for CD-8 and CD-4 T-cells and pigmented macrophages. In mice induced with LLC tumor and treated with saline, large tumor masses were observed in the lungs, and the calculated average tumor burden was 0.883g. Administration of VB-111 at 1x109 and 1x1011 VPs reduced tumor burden by 42% and 72% respectively. Concurrently, the number of tumor infiltrating CD8 T-cells was increased in correlation with VB-111 treatment dose.
Conclusion: Pre clinical and clinical data suggest that VB-111 induces an Immunotherapeutic effect manifested locally with tumor infiltration with CD-8 T-cells, and evidence of tumor necrosis. The viral vector may promote transformation of the tumor microenvironment from immunologically "cold" to "hot", enhancing immune cell recognition and immune activation.
Citation Format: Ronnie Shapira-Frommer, Tamar Rachmilewitz Minei, Iris Barshack, Itzhak Mendel, Niva Yakov, Yael C. Cohen, Eyal Breitbart, Dror Harats, Richard T. Penson. Ofranergene Obadenovec (VB-111), an anti-cancer gene therapy, induces immunologic responses in solid tumors transforming cold tumors to hot tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4979.