Abstract 2879: A novel therapeutic approach to treat patients with Type I interferon autoantibodies

Abstract Type I interferons (IFNs) are a group of nonredundant pleiotropic cytokines that play an important role in eliciting antiviral responses and have also been shown to have antineoplastic effects. Deficits in this signaling pathway have been shown to increase susceptibility to viral infection and decrease immune surveillance to block tumorigenesis. Prior studies demonstrate that inhibition of the type I IFN pathway markedly compromises the anti-neoplastic effects of chemotherapies, such as anthracycline-based drugs like doxorubicin, and dramatically decreases the number of tumor-free mice in experimental settings. Recent large-scale clinical studies revealed that circulating anti-type I interferon autoantibodies capable of neutralizing type I IFN signaling contributed to disease severity in patients infected by SARS-CoV-2 and may be responsible for nearly 20% of COVID-19 deaths. These IFN autoantibodies were directly capable of hindering innate antiviral responses, thus allowing viral replication to occur more robustly and spread to distal tissues. Additional studies revealed that these type I IFN autoantibodies are quite prevalent in the aging population, found at high levels in nearly 1 in 15 over the age of 65 and confer a 100-fold risk of severe life-threatening viral illness. Despite their high prevalence and ability to block IFN signaling, no study to date has examined the role of type I IFN autoantibodies in cancer progression and tumor response. Here, we investigate whether neutralizing type I IFN autoantibodies can block critical innate immune signaling pathways that result in a higher conversion of pre-malignant cells to malignant tumors. We hypothesize that carriers of type I IFN autoantibodies may respond poorly to primary anticancer therapies, including standard chemotherapy regimens and immunotherapies. Furthermore, using a first-in-class therapeutic decoy, we test whether blockade of type I IFN autoantibodies can provide a synergistic benefit when combined with standard anticancer agents. Citation Format: Eduardo Garcia-Reino, Nicholas Gao, Thanuka Udumulla, Elie Sosa, Nana Ayoluwa, Pargol Mashati, Andrew Patera, Jean-Laurant Casanova, Prem Premsrirut. A novel therapeutic approach to treat patients with Type I interferon autoantibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2879.