Abstract A043: Combination of immune agonist-containing nanoparticles and sitravatinib to treat high-risk neuroblastoma

Abstract High-risk neuroblastoma has a detrimental diagnosis for children, with a 50% 5-year survival rate driven primarily by metastasis, the largest hurdle for clinical treatment. Here, we present the combination of orally administered sitravatinib with intravenously delivered dual immune agonist-containing lipid-based nanoparticles (immuno-NPs) as a systemic immunotherapy. Immuno-NPs are loaded with monophosphoryl lipid a, a toll-like receptor 4 agonist, and cyclic di-GMP, a stimulator of interferon genes agonist. Uptake of these agonists by antigen-presenting cells promotes the production of type 1 interferons in the tumor microenvironment (TME), engaging innate immune cells within and around the TME to drive the characteristically cold, immunosuppressive neuroblastoma into a hot, immune-infiltrated state. This shift, the mounting of a vigorous immune response, leads to the recruitment of the effector cells to the tumor and metastatic sites which current treatment modalities struggle to accomplish. The second modality, sitravatinib, is a receptor tyrosine kinase inhibitor targeting multiple receptor tyrosine kinases including discoidin domain receptor 2 (DDR2); previous research has implicated this receptor as an auxiliary protein involved in metastasis for breast cancer. Through extrapolation, we believe DDR2 plays a similar role in neuroblastoma through its modulation and subsequent linearization of collagen fibers in the extracellular environment facilitating metastasis and augmentation of the epithelial-mesenchymal transition (EMT). Furthermore, sitravatinib has been suggested to alleviate immune suppression holding promise for synergistic impact when combined with immuno-NP treatment. We have previously tested our combination immunotherapy in the syngeneic 9464D-GD2 tumor model and humanized mouse SH-SY5Y orthotopic model. Our results have demonstrated the promise of this combination: an increase in the survival time of combination-treated groups and a reduction of tumor volume. Additionally, we have expanded to conducting survival studies of our combination immunotherapy in melanoma and breast cancer models, demonstrating the utility of our immunotherapy for other highly metastatic cancers. Our ongoing mechanistic studies include quantification of EMT inhibition in the primary tumor, collagen remodeling in the TME, and reversal of immune cell suppression after therapy. Our current data supports a programmatic shift to a hot TME signified by the increased presence of cytotoxic t cells within the tumor. In conjunction, we have preliminary data suggesting the efficacy of our immunotherapy in driving cells toward an epithelial phenotype confirmed by adhesion protein expression. We hypothesize our current mechanistic studies will confirm the linearization of collagen in the TME and its reversal in combination-treated groups. Herein, we have developed a combination immunotherapy platform with efficacy in treating high-risk neuroblastoma and other metastatic cancers and are elucidating its mechanism of action. Citation Format: Miranda B Diaz-Infante, Kim Wigglesworth, John Lukas, Griffin Kane, Meghan Brassil, Christina Lusi, Christian Alarcon, Jason Shohet, Prabhani U Atukorale. Combination of immune agonist-containing nanoparticles and sitravatinib to treat high-risk neuroblastoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A043.