W185 - Myeloid-directed Innate Immunotherapy Enables Immune Rejection of Bladder Tumors

Abstract Text: High-risk non-muscle invasive bladder cancer (NMIBC) is commonly treated with intravesical Bacille Calmette-Guérin (BCG) therapy. However, treatment failure and chronic BCG shortages leave many patients without effective options. To address this unmet need, we developed a triple-loaded nanoparticle system, CANDI, designed to enhance anti-tumor immunity through dendritic cell (DC) stimulation. CANDI incorporates R848, a TLR7/8 agonist, LCL-161, a cIAP inhibitor, and ruxolitinib, a JAK1/2 inhibitor, targeting canonical and non-canonical NF-κB pathways to upregulate IL-12 production.
In vitro studies using bone marrow-derived dendritic cells (BMDCs) from IL-12 reporter mice confirmed that triple-loaded CANDI significantly boosts IL-12 production compared to dual-drug formulations, with enhanced activation of DCs. In vivo, CANDI demonstrated robust therapeutic efficacy in MB49 bladder cancer models. Mice treated with CANDI exhibited significant tumor size reduction, enhanced IL-12 production, and increased activation and trafficking of DCs to tumor-draining lymph nodes (tdLNs). This led to improved antigen presentation and T cell priming.
CANDI was effective in both intravesical and intravenous administration routes, showing similar tumor targeting and immune cell activation. In a metastatic bladder cancer model, CANDI treatment reduced tumor burden, improved survival, and enhanced immune activation in the lungs and tdLNs. Mechanistic studies revealed that CANDI partially depends on CD8+ T cells for efficacy and requires DC trafficking from lymph nodes to the tumor site.
These findings highlight the potential of triple-loaded CANDI as a versatile therapeutic platform for both localized and metastatic bladder cancer, offering a promising alternative to current treatments like BCG.