Abstract 3271: Targeted cancer therapy using a novel recombinant il-24s/il-15 chimeric fusion cytokine

Abstract Melanoma Differentiation Associated Gene-7/Interleukin-24 (IL-24) and IL-15 provide therapeutic benefit in treating specific cancers. IL-24 displays cancer-specific apoptosis/toxic autophagy-inducing properties in a broad spectrum of human tumors without harming normal cells. IL-15 induces both differentiation and proliferation of T lymphocyte (T) and natural killer (NK) cells, enhances the cytolytic activity of CD8+ T cells, and induces the maturation of dendritic cells (DCs). In vivo administration of IL-15 has antitumor effects in several mouse tumor models; however, administration of IL-15 alone is not optimal. Various combination strategies have been explored to increase the efficacy of IL-15 immunotherapy, including coadministration of other cytokines or inhibitory antibodies against immune-suppression molecules. These approaches enhance antitumor responses as compared with IL-15 alone. Using an engineered form of IL-24 (IL-24S; a Superkine) that is secreted more robustly and is more stable, we created a recombinant IL-24S/IL-15 fusion construct in which IL-24S and IL-15 are linked by a flexible linker. This fusion construct was introduced into an adenovirus type 5 for effective delivery and expression. In the present study, we used focused ultrasound (FUS) paired with microbubbles (MB) to deliver the adenoviruses equipped with the IL-24S/IL-15 fusion construct into the mouse brain containing glioblastoma (GBM) and compared the antitumor effect of IL-24S/IL-15 with the individual factors IL-24S and/or IL-15. IL-24S/IL-15 displayed higher antitumor activity and survival benefits than the combination of the individual cytokines in GBM cancer models. There was a significant induction of apoptosis of cancer cells as well as an increase in tumor infiltration of T cells, DCs, Macrophages and NK cells. Antibody neutralization indicates that a primary immune mediator of anticancer activity of FSK is through recruitment and activation of NK cells. However, unlike immunocompetent mice, there was no increase in the survival rate by IL-24S/IL-15 when compared to the IL-24S or IL-15 treated group in SCID mice. Therefore, the increase in the survival rate by IL-24S/IL-15 in immunocompetent mice was achieved through the regulation of the anti-tumor immune response. Global cytokine analyses indicated no changes in inflammatory cytokines during therapy, suggesting that this strategy will be safe. In addition, IL-24S/IL-15 treatment resulted in enhanced GBM cell death vs. the individual cytokines. The antitumor inducing activity of IL-24S/IL-5 is likely due to induction of cancer-specific apoptosis (a function of IL-24S) as well as diverse effects on immune cells (both IL-15 and IL-24S). In summary, IL-24S/IL-15 may provide a new therapeutic reagent to enhance antitumor immunity and treat cancer. Citation Format: Amit Kumar, Padmanabhan Mannangatti, Swadesh K. Das, Paul B. Fisher. Targeted cancer therapy using a novel recombinant il-24s/il-15 chimeric fusion cytokine [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 3271.