Abstract 6713: Oncolytic adenoviruses expressing immune modulators enhance tumor cell killing in human cancer 3D microtumor models

Abstract

A series of investigational oncolytic immunotherapies based on DNX-2401 (tasadenoturev) are under development for the treatment of advanced cancers. Viruses “armed” with cell surface or secreted immune modulatory molecules inserted in the DNX-2401 backbone were evaluated using human cell derived 3D microtumor/ T cell models to elucidate specific anti-tumor properties and determine differences in immune activation. Background: DNX-2401 is a conditionally replicative adenovirus serotype 5 containing: 1) a 24 bp deletion from the E1A gene (Rb-binding domain) to confer cancer cell selectivity, and 2) insertion of an integrin-binding motif (RGD-4C) in the fiber to enhance infectivity across a broad range of cancers. DNX-2401 selectively replicates in cancer cells, causes tumor destruction, and triggers the recruitment of lymphocytes, leading to anti-tumor response. Phase 1 and 2 studies of DNX-2401 are ongoing in patients with glioblastoma and diffuse intrinsic pontine glioma. The first immune modified virus in the series, DNX-2440, engineered to express OX40L, is being evaluated in a Phase 1 study in patients with glioblastoma. Results: Immune modulator coding sequences inserted in place of E3 in the DNX-2401 backbone expressed properly localized and biologically active transgenes. DNX-2440 infected tumor cells expressed OX40L localized to the cell surface capable of stimulating OX40-expressing T cells. Tumor cells infected with a second virus, which was engineered to express a cytokine, secreted high levels of active protein. Both armed viruses showed infection, replication, and oncolytic activity in a panel of cancer cell lines under standard culture conditions. 3D microtumors composed of melanoma or lung cancer cells and normal human dermal fibroblasts were utilized to assess immune activation following virus infection. Unstimlated or pre-stimulated human immune cells were co-cultured for 12 days with the 3D microtumors infected with DNX-2401 or each armed virus. Infection with DNX-2440 increased T cell-mediated killing of tumor cells that was dependent on OX40/OX40L engagement, as the effect was abrogated in the presence of an OX40L blocking antibody. The kinetics of oncolytic activity, immune cell activation, and tumor infiltration were dependent on the immune modulator expressed from the oncolytic virus, resulting in differences in tumor clearance. These results demonstrate how oncolytic viruses can be customized to have unique properties by inserting different immune modulators into the virus genome, thus providing a customized approach for treating different cancers. Citation Format: Laura K. Springgay, Amy M. Strauwald, Brett Ewald, Joan M. Robbins, Winnie M. Chan. Oncolytic adenoviruses expressing immune modulators enhance tumor cell killing in human cancer 3D microtumor models [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 6713.

Trial watch: intratumoral immunotherapy

“…Oncolytic adenoviruses are also combined with other treatments in the clinic ( Table 2 ). 224 NCT04714983 evaluates DNX-2440 (expressing OX40L) 225 in patients with resectable multifocal liver metastasis scheduled for curative-intent liver resection surgery. NCT03225989 studies LOAd703 (encoding a trimerized membrane-bound extracellular CD40L and 4–1BBL) 226 in colorectal, biliary, ovarian, or pancreatic cancer together with gemcitabine immune-conditioning or standard of care chemotherapy.…”

OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment

“…Nevertheless, OX40 agonist therapy in pancreatic cancer is hindered by inefficient T cell trafficking into tumor immunosuppressive TME. DNX-2440, an OX40 ligand expressing oncolytic adenovirus, triggered an anti-tumor immune response and led to prolonged survival in preclinical models of cancers such as gliomas 19 . In addition, virus-like particles (VLPs) harboring OX40 ligand showed potential for boosting T-cell activation and eliminating tumor cells 20 .…”