Abstract 2705: Low-dose crystalline cytokine macrophage mediated Trojan horse immunotherapy of solid cancers

Abstract

Abstract Protein therapeutics are often compromised by sub-optimal biodistribution contributing to poor efficacy and adverse events. Drug delivery mechanisms better able to target the disease site and provide localized, sustained drug release have the potential to transform therapeutic standards. PODS crystals (PCs) are natural-mimetic, micron-scale protein co-crystals engineered to incorporate a protein cargo that is sustainably released under the action of resident proteases. PCs are efficiently taken up by phagocytic cells and their cargo protein is subsequently released in a bioactive form. Since blood-circulating phagocytic cells, including monocytes, are actively recruited into the tumor microenvironment, we postulated that monocyte/macrophage-mediated PC delivery could be used as a molecular “Trojan horse” to efficiently deliver therapeutic proteins to target cells. This could improve the pharmacodynamics and pharmacokinetics of protein drug delivery to treat systemic and disseminated diseases. Interleukin-2 (IL-2) is notoriously toxic at the high doses required for therapeutic efficacy. Here, we demonstrate the therapeutic efficacy and tolerability of low doses of PC-IL-2 administered intravenously in a mouse model of melanoma. We further demonstrate the therapeutic benefit of PCs delivering low doses of IL-2, interleukin-15 (IL-15) and interferon-gamma (IFN-γ) in a mouse model of renal cell carcinoma. In all the treated mice, cachexia, a side effect of high-dose cytokine therapy, was notably absent. This study provides proof-of-concept for the utility of intravenously administered PCs to provide a generalised and widely applicable mechanism to effectively deliver protein drugs for the therapy of cancer and other diseases. Citation Format: Michael H. Jones, Nirk E. Quispe Calla, Callum Talbot-Cooper, Hong Zeng, Jonathan Best, Robert Smith. Low-dose crystalline cytokine macrophage mediated Trojan horse immunotherapy of solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2705.