Minimally invasive pancreatic cancer treatment combining nanosecond electric pulses and immune system stimulants

SUMMARY Despite the significant recent advances in personalized medicine, pancreatic ductal adenocarcinoma (PDAC) remains near-uniformly lethal. This unfortunate prognosis is attributed to an aggressive local tumor growth in addition to an early systemic spread of tumor metastases1. Nearly 50-60% of patients present with distant metastatic disease at the time of diagnosis and only 4-16% are candidates for surgical resection2. Chemotherapy and/or radiation therapies provide only mild clinical benefits2, and pain remains the most distressing symptom of pancreatic cancer, affecting 30-40% of patients. We are proposing a non-surgical approach that aims to address the desperate need for the primary treatment of pancreatic cancer and palliative care. Specifically, our main goal is to develop a new, two-component treatment for PDAC that employs endoscopic ultrasound to guide a unique bipolar catheter to the tumor to: 1) deliver nanosecond electric pulses to the pancreatic tumor; and 2) Inject an immune system stimulant into the tumor to generate an in situ vaccine that exploits the immunogenic cell death triggered by nanosecond electric pulses and stimulates the immune system to attack any untreated tumors. Specifically, we have discovered an electric pulse that is 1000-fold faster and 30-fold larger than conventional electroporation pulses, enabling its penetration into cellular organelles. This high-intensity nanosecond pulsed electric field pulse known as Nano-Pulse Stimulation (NPS), disrupts the cell plasma and organelle membranes, leading to irreversible changes in homeostasis and regulated cell death. NPS ablation is safe, efficient, and non- thermal and, thus, particularly promising for treating tumors, including those located in thermally sensitive organs with high vascularity and structural density, such as the pancreas. The basis for the success of NPS treatments is thought to be the direct killing of tumor cells by reversible electroporation of the organelle membranes. This application aims to develop a catheter that can deliver NPS and immune stimulants to the pancreatic tumor. We will also identify the optimal concentration of immune stimulants to inject into NPS-treated murine tumors to determine the most effective combination to eliminate untreated tumors. Our preliminary data suggest that this combination therapy has the best chance of enlisting the immune system to recognize tumor antigens and attack metastases and untreated regions of the primary tumor. The key elements in this approach are the release of tumor antigens by immunogenic NPS ablation that are picked up by a hyper-stimulated immune system to initiate a stronger antigen immune response that will attack untreated tumors.