Abstract 3565: Viroimmunotherapy for solid tumors results in local and abscopal anti-cancer effects and the remodeling of tumor microenvironment
Authors: Van Wieren Arie C. , Sahoni Sagar , Nguyen Teresa , Ossimetha Ashley , Rivera-Molina Yisel , Jiang Hong , Shin Dong Ho , Kim Debora , Fan Xuejun , Yi Yanhua , Melendez-Vazquez Natalie M. , Godoy-Vitorino Filipa , Gumin Joy , Lang Frederick F. , Alonso Marta M. , Fueyo Juan , Gomez-Manzano Candelaria 
Published: June 2022

Abstract
Oncolytic viruses are a promising experimental treatment for solid tumors. Recently, several phase 1 clinical trials have reported encouraging therapeutic effects of oncolytic viruses in adult and pediatric patients with malignant gliomas. To further improve the therapeutic outcome of viroimmunotherapy, we have developed Delta-24-RGDOX (DNX-2440), a replication competent adenovirus encompassing the T-cell activator OX40L in the genetic backbone of Delta-24-RGD. We have previously reported the effect of Delta-24-RGDOX in murine brain tumors supporting the translation of this new agent to treat patients with recurrent malignant gliomas (NCT03714334). In the work presented here, we have tested the therapeutic effect of Delta-24-RGDOX in murine syngeneic models of breast (4T1), gastric (M12) and lung cancer (LLC and CMT 167). We found that Delta-24-RGDOX infected all cancer cell lines efficiently. In addition, infection of cells was followed by the expression of the ectopic ligand in vitro and in vivo. Because the elicitation of an anti-tumor immunity is part of the mechanisms underlying the therapeutic effect of oncolytic viruses, we examined whether infection of tumors led to the reshaping of the tumor microenvironment. We observed that Delta-24-RGDOX infection was followed by increased frequencies of tumor infiltrating lymphocytes, particularly CD8+ T cells and NK cells. In addition, the CD8+/CD4+ ratio was increased in Delta-24-RGDOX-treated tumor versus PBS-treated tumors. Interestingly, abscopal modifications were observed in breast cancer brain metastases with increased frequency of CD8+ T cells at the distal, untreated site. Delta-24-RGDOX treatment induced an anti-cancer effect in orthotopically implanted breast cancer and subcutaneously implanted lung and gastric tumors, as well as in metastatic niches. In summary, our data showed that treatment of solid tumors with Delta-24-RGDOX induces robust remodeling of the tumor microenvironment and produces anti-tumor effects leading to decrease in tumor volume, along with a delay in the development and in the reduction of the number of metastases. These data suggest that Delta-24-RGDOX should be tested in the clinical setting in patients with metastatic breast, gastric and lung cancers.
Citation Format: Arie C. Van Wieren, Sagar Sahoni, Teresa Nguyen, Ashley Ossimetha, Yisel Rivera-Molina, Hong Jiang, Dong Ho Shin, Debora Kim, Xuejun Fan, Yanhua Yi, Natalie M. Melendez-Vazquez, Filipa Godoy-Vitorino, Joy Gumin, Frederick F. Lang, Marta M. Alonso, Juan Fueyo, Candelaria Gomez-Manzano. Viroimmunotherapy for solid tumors results in local and abscopal anti-cancer effects and the remodeling of tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3565.