Intratumoral administration of IL-2 and IL-33 mRNA via lipid-like nanoparticles induces robust and persistent anti-tumor immunity 3175

Abstract Description Cytokine-based immunotherapies for solid cancers including melanoma can promote complete responses in a small subset of patients, but systemic administration of high doses can lead to severe toxicities. Localized therapy delivers cytokines directly to the tumor microenvironment (TME), maximizing drug bioavailability and limiting adverse events. We previously discovered that interleukin-2 (IL-2), a well-defined T cell growth factor, and IL-33, a tissue alarmin, synergize to reduce primary solid tumor growth in vivo. Here, we evaluate a cell-free delivery system by encapsulating IL-2 and IL-33 mRNA in a novel N1,N3,N5-tris(3-(didodecylamino)propyl) benzene-1,3,5-tricarboxamide (TT3) derived lipid-like nanoparticle (LLN) (TT3-LLN-IL-2+IL-33). We show that intratumoral administration of TT3-LLN-IL-2+IL-33 promotes B16F10 melanoma tumor control as a single-agent therapy by inducing robust infiltration of innate and adaptive immune cells and shifts the TME from immunosuppressive to immunostimulatory. Importantly, local IL-2 and IL-33 expression generated durable and systemic anti-tumor immunity that fully protected against a secondary B16F10 challenge on the opposite flank. Thus, intratumoral administration of TT3-LLN-IL-2+IL-33 effectively promotes immediate and persistent anti-tumor immunity, rendering it a promising off-the-shelf treatment strategy for solid cancers. Funding Sources NIH/NCI CA271553 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)