Abstract
Pancreatic duct adenocarcinoma (PDAC) poses significant challenges in oncology, with a dismal five-year survival rate of merely 12.5%. Standard treatments, including fluorouracil and gemcitabine-based chemotherapies, often fail to produce lasting responses. Checkpoint inhibitors, despite their success in other solid tumors, have not improved outcomes in PDAC patients, primarily due to the tumor's immunosuppressive microenvironment, rendering it "cold" and resistant to immune system attacks. To address this, dendritic cell (DC) vaccination emerges as a promising immunotherapy approach. DCs, capable of activating natural killer (NK) cells and CD8+ T cells, could potentially reinvigorate the antitumor immune response, thus improving patient outcomes. Current DC vaccines are typically prepared from autologous monocytes, which are differentiated and loaded with tumor-associated antigens (TAAs) such as the Wilms' tumor 1 (WT1) gene. WT1 is recognized as a priority antigen for cancer immunotherapy, yet its efficacy is often limited. The role of recombinant cytokines, particularly Interleukin-15 (IL-15), is gaining attention for its ability to enhance immune responses. IL-15 is instrumental in stimulating both innate and adaptive immune components, including NK and T cells, and enhancing the survival of memory T cells. However, the short half-life of IL-15 presents challenges for clinical applications. Pre-complexation of IL-15 with its receptor IL-15Rα can extend its half-life and enhance its bioactivity, offering a more effective delivery mechanism for cancer treatment. An academic clinical trial (NCT05964361) is currently ongoing at University Hospital Antwerp to evaluate the safety and feasibility of an IL-15-transpresenting WT1-targeting autologous DC vaccine in patients with advanced pancreatic cancer. This trial aims to combine the strengths of DC vaccination and IL-15 to tackle the immunosuppressive nature of PDAC. Given that traditional DC vaccines primarily stimulate T-cell responses, integrating IL-15 could also enhance NK cell activation, addressing the underutilization of these immune effector cells. The overarching goal of this research is to elucidate the immunological mechanisms behind the IL-15-transpresenting DC vaccine's efficacy in PDAC. The specific objectives include mapping the shifts in immune cell composition and activation post-vaccination, characterizing molecular changes in the T cell receptor (TCR) repertoire, and integrating immunological findings with clinical data to identify predictive biomarkers for treatment response. By enhancing our understanding of the immune responses elicited by this innovative therapy, this project seeks to improve DC vaccine effectiveness, ultimately offering new hope for PDAC patients facing limited treatment options. This interdisciplinary approach has the potential to transform treatment paradigms in pancreatic cancer, paving the way for more personalized and effective immunotherapeutic strategies.
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