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To better evaluate complex immunotherapies in a human\u2010relevant setting, we developed an integrated organoid\u2013immune co\u2010culture pipeline using PDAC patient\u2010derived organoids (PDOs) and matched HLA immune cells. As a proof of concept, we assessed an MSLN\u2010targeted nanovaccine (Mesovac), alone and in combination with FOLFIRINOX chemotherapy and Atezolizumab. We evaluated Mesovac across a multi\u2010stage pipeline, including T\u2010cell stimulation, ex vivo expansion, and PDO\u2010immune co\u2010cultures, to assess immune activation, specificity, and synergy with combinatorial treatments. MSLN\u2010stimulated T\u2010cells, derived from PDAC patients, showed increased IFN\u2010\u03b3 production and selective infiltration into MSLN\u2010expressing PDOs. Artificial antigen\u2010presenting cells (aAPCs) boosted the expansion of reactive T\u2010cells, enhancing antitumor responses. 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