DC-Targeted Nanovaccine Enhances Immunity and Efficacy of SoC and KRAS-Targeted Therapies in PDAC
​
1 Department of Physiology and Pharmacology, Tel Aviv University
2 Gray Faculty of Medical and Health Sciences
3 Department of General Surgery, Tel Aviv Sourasky Medical Center,
Objectives: Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate due to its immunosuppressive nature and resistance to chemotherapy. To address this, we developed a dendritic cell (DC)-targeted nanovaccine (NV) to boost anti-cancer immunity.
Methods: The NV is composed of biodegradable polymers (PLGA/PLA) functionalized with mannose for targeted uptake by DCs and co-loaded with TLR agonists and PDAC-specific peptides derived from CEACAM5 protein, overexpressed in >90% PDAC cases. The NV efficacy was assessed on mice and patient-derived models, following physicochemical characterization, which demonstrated a diameter of 180 nm and preclinical safety.
Results: The NV induced significant changes in vivo in PDAC’s TME, such as increased effector cells, including CD8 T cells, and decreased regulatory cells, such as Tregs and myeloid-derived suppressor cells. Combining the NV with chemotherapy (Gemcitabine/Nab-Paclitaxel) or targeted therapy (KRAS G12D inhibitor) further enhanced therapeutic outcomes compared to monotherapy. The combination therapy significantly repressed tumor growth and prolonged survival in an orthotopic model. From the proteomic analysis of the serum from NV-treated mice, we found five significant genes that participate in antigen processing and presentation, suggesting systemic activation of the immune system by the NV. Furthermore, we established a patient-derived ex vivo model using autologous PBMCs and 3D tumor spheroids to evaluate NV efficacy. This unique 3D model enabled us to assess ex vivo the NV‘s effect on PDAC patient samples. We show that CECAM5 NV-activated T cells decrease 3D-spheroid size and increase IFN-γ secretion as well as Caspase-3 expression on cancer cells compared to untreated T cells. Conclusions: Our NV induced a strong antigen-specific immune response and limited tumor growth while reshaping PDAC’s immunosuppressive TME. Our 3D patient-derived model enables assessment of NV-driven immune responses and drug combinations in a clinically relevant context. This platform offers a strategy to generate robust immunity in cold tumors like PDAC.