Document resource
Background We have created an mRNA lipid nanoparticle aggregate (RNA-LPA) therapeutic that has shown efficacy in preclinical models and has entered phase I clinical trials ( NCT04573140, NCT05660408). Mitigation of associated toxicities such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) is necessary for safe administration, and we aimed to assess the effect of mitigation strategies in our preclinical models. We hypothesized that cytokine blockade could potentially dampen innate immunity and limit toxicity while enhancing adaptive anti-tumor efficacy.Methods We utilized the K7M2 osteosarcoma model in Balb-c mice and a cell dose of 1.25 million cells injected via tail-vein and RNA-LPA (administered intravenously) with or without cytokine blockade (administered intraperitoneally) on days 4, 7, 10, and then weekly. Treatment groups (n=8 each) included: 1) untreated, 2) RNA-LPA alone, 3) RNA-LPA + IL-1R blockade, 4) RNA-LPA + IL-6R blockade, and 5) RNA-LPA + combination blockade. Peripheral blood following 5th vaccine and splenocytes from mice at endpoint were analyzed by flow cytometry and cytokine analysis.Results Mice frequently developed signs of cytokine-mediated toxicity similar to clinical CRS observed in human patients within 24-48 hours after 4th vaccine. Based on objective signs observed in mice, we developed a scoring system for murine CRS ( table 1).Following RNA-LPA priming doses, administration of IL-6 blocking antibodies did not abrogate anti-tumor efficacy. Similarly blockade of IL-1 did not attenuate anti-tumor efficacy of infusions. These results were critical for management of human subjects developing CRS on study for glioblastoma (NCT04573140) and osteosarcoma patients (NCT05660408)Conclusions Targeted inhibition of IL-6 may enable continued immunotherapy without comprising mRNA vaccine activity.Abstract 1041 Table 1Scoring system for murine CRS