Author(s): John Michael Bryant, Qianxing Mo, Alicia Chin, Pamela Hodul, Jason Denbo, Daniel Anaya, Jason Fleming, Jose M. Pimiento, Andrew Sinnamon, Ji Fan, Dae Won Kim, Richard Kim, Tiago Biachi de Castria, Mohammed Al-Jumayli, Martine Extermann, Christine Sam, Barbara Centeno, Krystal Villalobos-Ayala, Jennifer B. Permuth, Tomar Ghansah, Paulo C. Rodriguez, Joel S. Brown, Solomon Alhassan, Aamir Dam, Shaffer Mok, Anjuli Luthra, Saras Cappelle, Fawn D. Vigneau, Ola M. Gaber, James Costello, Bela Kis, Junsung Choi, Jessica M. Frakes, Sarah Hoffe, Robert A. Gatenby, Mokenge Malafa*
Introduction: Pancreatic Adenocarcinoma (PDAC) is one of the most lethal malignancies, with a dire need for new treatments. Locally Advanced Pancreatic Cancer (LAPC) often presents with limited therapeutic options, with median overall survival of only 6 to 11 months. Immunotherapy (IO) has shown promising results in various solid and hematological malignancies, but it is less effective in PDAC because of its immunosuppressive Tumor Microenvironment (TME) and cold tumor phenotype. This study explores the efficacy of Irreversible Electroporation (IRE) combined with IO in altering the TME, following standard-of-care Chemotherapy (CHT) and Radiation Therapy (RT), to enhance treatment response in LAPC.
Methods: This is a nonrandomized, single-arm, Phase 1 study for adult patients with histologically confirmed LAPC. The treatment involves a nonconcurrent combination of CHT, RT, IRE, and IO with pembrolizumab. The study assesses the safety, tolerability, and preliminary efficacy of this combined sequential therapy. Biopsies taken at the time of IRE and after IO, along with blood and serum samples taken regularly throughout therapy, will be used to assess changes in therapeutic responses in the TME and to identify both immunologic and tumor markers.
Discussion: The study hypothesizes that using a multistrike strategy will induce permanent alterations within the PDAC TME, turning it from cold to hot via RT and IRE to enhance the responsiveness to IO. This approach is based on evolutionary dynamics models, drawing from Anthropocene extinction events. If successful, this trial can not only improve LAPC outcomes but also contribute to the understanding of the biology of LAPC, potentially leading to the development of personalized therapies for LAPC. If successful, results from this study will lead to a Phase 2 randomized trial to further evaluate the efficacy of this treatment approach and contribute to the identification of novel biomarkers for personalized treatment strategies.
