Locoregional Irreversible Electroporation for Macrophage-Mediated Immunotherapy of Early-Stage Bladder Cancer
Abstract
Our proposal addresses the following Fiscal Year 2019 Peer Reviewed Cancer Research Program Topic Areas: Bladder Cancer and Immunotherapy The proposed research is relevant to active duty Service members and Veterans who are at high risk for developing bladder cancer due to unique environmental exposure to toxins and heavy metals, as well as work-associated risk factors. Early stage and localized non-muscle invasive bladder cancer (NMIBC) is the initial diagnosis in over 70% of all bladder cancer patients. The standard of care is to remove the tumor visible on ureteroscopic imaging with minimally invasive surgery, followed by intra-bladder administration of chemotherapy or immunotherapy with the Bacillus Calmette–Guérin (BCG) vaccine to treat widespread microscopic tumors or diseased cells present throughout the inner urothelial layer lining the bladder. Despite their cancer being detected at an early stage, the majority of NMIBC patients will experience recurrence of tumors in their bladder and remain at elevated risk of developing aggressive, metastatic disease. While T cell immunotherapy has revolutionized the treatment of cancer, 40 years of clinical experience with the BCG treatment and the early results from checkpoint inhibitor trials reveal a considerable rate of non-responders, the lack of durable cure and significant treatment related toxicity as limiting factors. Macrophages are part of our immune system, and these cells are capable of killing cancer cells without the need for the complex series of steps and conditions that are required to initiate and sustain T cell immunotherapy. However, increased infiltration and presence of macrophages in the bladder, high macrophage to cancer cell ratio, and favorable macrophage activation status are crucial conditions that are required to enable macrophage mediated immunotherapy (MMI) of NMIBC and other malignancies. Our objective is to address the critical gap in NMIBC therapy by developing new technology for the locoregional application of irreversible electroporation (IRE) in the bladder to generate an immuno-microenvironment favorable for MMI, independent of patient or tumor characteristics. IRE is already used by physicians for the minimally invasive treatment of tumors in a procedure called ablation, where ultrashort electric pulses are delivered using needle electrodes to kills cells within a tumor by creating nano-sized pores in their membrane. A unique feature of IRE is that its treatment effect is restricted to cells, therefore large blood vessels and the extracellular scaffold around the cells remains unaffected, supporting the penetration of immune cells into the site of treatment. Based on preliminary work performed in the Principal Investigator’s (PI’s) lab that shows that IRE can increases macrophage population in both healthy urinary tract in swine and murine urothelial tumors in mice, we rationalize that IRE is an ideal tool to recruit macrophages that can be harnessed (work performed in the Co-PI’s lab) to eliminate cancer throughout the bladder. Our central hypothesis is that injury to cancerous cells with IRE will release molecules and proteins that will attract macrophages, which can be harnessed for anti-cancer function by reprogramming them to have a “M1” or inflammatory function using a nanoparticle therapeutic, where we will use specially designed catheter mounted electrodes to allow the repeated, minimally-invasive application of IRE throughout the entire bladder to prevent recurrence by eliminating all cancerous cells with the reprogrammed macrophages. We will investigate this hypothesis by using in vitro studies using human cancer cells specifically selected for their varied molecular characteristics in co-culture with macrophages, computer simulation models, in vitro 3D printed bladders, mouse tumor models, and chemically induced bladder cancer in rats. The application of IRE to create an environment that favors macrophage-based kil
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010676
Entities
People
- Govindarajan Srimathveeravalli
Organizations
- United States Army
- University of Massachusetts Amherst