Cyclodextrin-Based Nano-Immunotherapy Enhances Dendritic Cell Activation to Drive Anti-Tumor Immunity in Bladder Cancer 2334395

Abstract

Abstract Introduction High risk non muscle invasive bladder cancer is commonly treated with intravesical BCG therapy, yet many patients fail treatment or develop recurrent disease. Effective anti tumor immunity in bladder cancer depends on dendritic cell activation and IL-12 production, which promotes T cell priming and effector function. We developed CANDI, a modular nanoparticle immunotherapy platform designed to deliver small molecule innate immune agonists directly to tumor antigen-presenting cells and enhance IL-12-driven immunity. Using optical screening, we identified a combination of innate stimulants that robustly induce IL-12. Unexpectedly, inclusion of the JAK inhibitor ruxolitinib further enhanced IL-12 production when co-delivered with innate agonists. Methods Bone marrow-derived dendritic cells from IL-12 reporter mice were used to quantify cytokine production following CANDI treatment. Therapeutic efficacy and immune responses were evaluated in orthotopic and metastatic MB49 bladder cancer models using intravesical and intravenous delivery. Tumor burden, dendritic cell migration, and T cell responses were assessed by imaging and flow cytometry. Results Triple combination CANDI significantly increased IL-12 production and dendritic cell activation compared to dual formulations. In tumor-bearing mice, CANDI reduced tumor burden, enhanced dendritic cell trafficking to tumor-draining lymph nodes, and improved antigen presentation and T cell priming. Comparable immune activation and tumor control were observed following intravesical and systemic delivery. In metastatic disease, CANDI reduced lung tumor burden and improved survival. Therapeutic efficacy was largely dependent on CD4 T cells, which amplified local IL-12 production by tumor resident dendritic cells. Conclusion Triple combination CANDI is a potent dendritic cell activating nano immunotherapy that drives durable anti tumor immunity and provides a rational strategy to overcome limitations of prior innate immune agonist therapies. Funding Source NIH, DOD, BICAN Topic Categories Vaccines and Immunotherapy (VAC)