Abstract 686: Immunostimulatory gene therapy with oncolytic viruses potentiates the effect of paclitaxel and cisplatin in ovarian cancer
Authors: Naseri Sedigheh , Härdin Jonas , Eriksson Emma , Lövgren Tanja , Ullenhag Gustav , Loskog Angelica 
Published: April 2023

Abstract
Ovarian cancer is commonly treated with debulking surgery, followed by a combination of a taxane and a platinum-based chemotherapy. However, &gt;70% of patients relapse within 3 years with tumors resistant to platinum-based agents. 5-year survival is ranging from 30-40%. Thus, delaying recurrence of disease is a high unmet need in ovarian cancer. Combining the chemotherapy regime with immunostimulatory gene therapy utilizing oncolytic viruses as gene vehicles is an attractive treatment option targeting alternative pathways to induce tumor cell death, control tumor growth and prevent development of metastasis. LOAd703 is an oncolytic adenovirus derived from the LOAd platform of replication-restricted Ad5/35 adenoviruses. LOAd703 encodes for the human immunostimulatory genes trimerized, membrane-bound CD40L (TMZ-CD40L) and 4-1BBL, expressed under a CMV promotor which enables gene expression in both tumor cells and tumor stroma while replication is restricted to tumor cells. Herein, we investigated the effect of combining LOAd703 with paclitaxel and cisplatin in vitro and in vivo. Four human ovarian cancer cell lines (CAOV3, COV362, OVCAR3 and PEA2) were treated with LOAd703 alone, in combination with paclitaxel and/or cisplatin or were left untreated. LOAd703 efficiently killed the ovarian cancer cell lines by oncolysis, as evaluated by an MTS cell viability assay. This effect was further improved when LOAd703 was given in combination with paclitaxel and/or cisplatin. Flow cytometry revealed that the ability of LOAd703 to induce expression of the immunostimulatory transgenes TMZ-CD40L and 4-1BBL, was not negatively affected by the combination with paclitaxel and/or cisplatin. The combination treatment was further tested in an in vivo model where BALB/c nu/nu mice were xenografted with 5 million OVCAR3 cells. The mice were subsequently treated with LOAd703 (1 × 10e9 FFU/mouse), both alone as well as in combination with paclitaxel (6mg/kg) and cisplatin (2.5mg/mg). The treatments were given over the course of 4 weeks where LOAd703 was administered intratumorally twice per week while chemotherapy was given intraperitoneally once per week. The results showed that the combination of LOAd703 and the chemotherapeutics controlled tumor growth significantly better than either LOAd703 alone or the standard treatment with paclitaxel and cisplatin. In conclusion, LOAd703 efficiently killed ovarian cancer cell lines in vitro, and could potentiate the effect of standard-of-care chemotherapy. This effect was confirmed in vivo, in which the combination therapy had a better tumor control than the other treatment groups. A clinical trial is ongoing to confirm the effect of adding LOAd703 to different treatment regimes in ovarian cancer (NCT03225989).
Citation Format: Sedigheh Naseri, Jonas Härdin, Emma Eriksson, Tanja Lövgren, Gustav Ullenhag, Angelica Loskog. Immunostimulatory gene therapy with oncolytic viruses potentiates the effect of paclitaxel and cisplatin in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 686.