LEVERAGING FOCUSED ULTRASOUND, IMMUNOTHERAPY AND BIOMATERIALS AS TREATMENTS FOR PANCREATIC CANCER

Pancreatic cancer is a devastating disease that has been baffling scientists for decades. Mechanisms of immune escape, including downregulation of antigen presentation, secretion of immunosuppressive cytokines, and expression of immunoregulatory molecules make it difficult to successfully develop immunotherapies for pancreatic cancer. Additionally, surgery is not curative, and patients become resistant to chemotherapeutic treatments. A desmoplastic stroma made up of extracellular matrix proteins acts as a physical barrier to prevent our body’s immune cells and drugs from penetrating the tumor. Therefore, the strategy of this thesis is to provide solutions to improve drug delivery to the tumor and to modulate the pancreatic tumor microenvironment from “cold” to “hot.” Throughout this thesis, we have used a variety of technologies as treatment strategies for pancreatic cancer, including in-situ forming implants (ISFIs), therapeutic ultrasound, and immunotherapy. First, we performed ISFI in vitro studies using twelve model drugs with various physicochemical properties to understand the effects on polymer degradation and drug release. This study led us to choose paclitaxel as a suitable drug for long-acting delivery of chemotherapeutics to pancreatic tumors. Next, we performed in vivo studies using ISFIs with the model drug dolutegravir to demonstrate the effects of injection volume, number of injections, and route of administration on pharmacokinetics. This study provides insight on future formulation parameters for pancreatic cancer ISFIs in vivo. The focus of the thesis switches to the utilization of therapeutic ultrasound and immunotherapy for tumor treatments. We thoroughly reviewed the literature to outline the bioeffects and immune responses that focused ultrasound can cause in tumors. Then, we used this information to design a study to understand the immune effects of low-intensity focused ultrasound and microbubbles (LoFU + MB) in subcutaneous pancreatic tumors. As a result of the recruitment of macrophages and T cells to the lymph node two days post-treatment, we combined LoFU + MB with CD40 agonist and immune checkpoint inhibitors, which resulted in a complete response in a small subset of mice. To increase the breadth of potential focused ultrasound treatments for use in pancreatic cancer, we optimized parameters to achieve four differing bioeffects in orthotopic pancreatic tumors. Future studies will seek to combine these bioeffects with immunotherapy to understand the effect on the pancreatic tumor microenvironment.