Abstract 6749: A dendritic cell targeted nanosystem to overcome immune suppression and enhance the efficacy of the standard of care for pancreatic cancer

Abstract The development of novel therapies for pancreatic ductal adenocarcinoma (PDAC) remains an urgent unmet medical need, as it was proven to be refractory to most conventional anti-neoplastic therapies. PDAC is characterized by highly dense stroma, immunosuppressive tumor microenvironment (TME), high resistance to chemotherapy, and poor presentation of tumor-associated antigens (TAA) by dendritic cells (DC), which results in low immune cell infiltration to the tumor site. To that end, we designed a DC-targeted nanovaccine (NV) containing PDAC TAA and TLR agonists to modulate the PDAC immune-microenvironment. In recent years, the combination of immunotherapy with chemotherapy has been explored for PDAC therapy to improve efficacy. Therefore, we demonstrate the effect of our NV on the anti-tumor immune-mediated response in PDAC-bearing mice, alone and in combination with Gemcitabine and Nab-Paclitaxel (Gem/NabP). Our DC-targeted NV was formulated by the double emulsion method and loaded with PDAC’s TAA and immune potentiators. We conjugated the NV to a mannose moiety as a targeting moiety for the mannose receptor expressed on DC to increase the NV uptake, which resulted in the enhanced presentation of the encapsulated TAA. Followed by physicochemical characterization and evaluation of preclinical safety of the NV, the stimulation of T cell-specific response against PDAC tumor was assessed in vivo and ex vivo. The NV induced significant changes in PDAC’s TME, such as increased CD8+ T cells, decreased CD4+ T regulatory cells, and induced memory immunity in the tumor site. The combination of NV and Gem/NabP inhibited tumor growth and prolonged survival compared to mice treated with Gem/NabP alone. This could also be related to the immunogenic cell death effect caused by the chemotherapies. In addition to our mice model of PDAC, we also established a patient-derived model, in which we generate 3D-spheroids from the patient’s tumor and activate PBMCs with our NV from the same patient. This unique 3D model enables us to evaluate ex vivo the NV effect in a more clinically relevant manner. The NV proposed herein could induce a strong antigen-specific immune response against PDAC with restricted tumor growth while re-shaping PDAC immunosuppressive TME. Furthermore, our 3D patient-derived PDAC model allows us to assess the ability of our NV to generate specific immune responses in patients and to test other possible drug combinations predicting the clinical outcome. Citation Format: Ron Kleiner, Daniella Vaskovich-Koubi, Rita Acúrcio, Barbara Carreira, Helena Florindo, Ronit Satchi-Fainaro. A dendritic cell targeted nanosystem to overcome immune suppression and enhance the efficacy of the standard of care for pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6749.