Durable antitumor response via an oncolytic virus encoding decoy-resistant IL-18

• DOI: 10.1136/jitc-2024-009716
• Publication Date: 2024-12-05T01:36:38Z
• Authors: Yan Cheng; Yuanhui Zhao; Yu Liu; Yichi Zhang; Dongge Xu; Weikang Sun; Mengyu Zhang; Yuqing Miao; Susu He; Yayi Hou; Dwayne Stupack; Erguang Li
• Keywords: Decoy; Oncolytic adenovirus

Background Interleukin-18 (IL-18), or interferon (IFN)-γ-inducing factor, potentiates T helper 1 and natural killer cell activation as well CD8 + T-cell proliferation. Recombinant IL-18 has displayed limited clinical efficacy in part due to the expression of decoy receptor, binding protein (IL-18BP). A series variants that are devoid IL-18BP binding, termed DR18 (decoy-resistant IL-18), was developed via directed evolution. We tested using oncolytic adenovirus (oAd) a platform for delivery syngeneic mouse tumor models. Methods oAd harboring wild-type (oAdDR18) constructed by inserting mutant into modified backbone with Ad5/3 chimeric fiber. The effect IFN-γ induction were determined ELISA. antitumor efficiency oAdDR18 CT26, B16BL6 4T1 tumor-bearing mice, athymic nude mice compared recombinant (rDR18). lung metastasis model used evaluate local distant tumors. Antitumor memory synergistic an anti-programmed death protein-1 (PD-1) antibody evaluated. phenotypes immune cells microenvironment analyzed flow cytometry immunohistochemistry. Results Mice received maintained stable production those rDR18. Intratumoral significantly reduced growth across several models, but not model. had remission showed memory. associated intratumor infiltration CD4 cells. delivered demonstrated long-lasting enhanced activities against tumors rDR18 (oAdwtIL-18). treatment also metastasis. In addition, combination this virotherapy checkpoint inhibitors (ICIs) like anti-PD-1 further activity respective monotherapy. Conclusions demonstrates through stronger system immunities modulation oAdwtIL-18 cytokine engineering would lead cytokine-based therapeutics cancer other diseases.