Determination of Immunotoxin GB13 Intratumoral Drug Distribution for the Treatment of Adult and Pediatric Brain Cancers
Abstract
Brain cancer is a deadly diagnosis that affects adults and children. We are focused on how to improve the outcomes for adult glioblastoma (GBM) and pediatric diffuse midline glioma (DMG) patients, who have very few treatment options and a poor survival prognosis. These cancer types are of interest because nearly 80% express a receptor called the interleukin 13 receptor alpha 2 (IL13Ra2). This receptor is not found on noncancerous cells of the body and, as such, we have developed a drug that binds this receptor. GB13 is an immunotoxin therapy that specifically targets IL13Ra2 on cancer cells and combines a toxin component that provides very sensitive cancer killing capability. Based on preliminary studies, GB13 has been granted Orphan Drug designation for malignant glioma brain cancers and is ready to be moved into clinical trials. One of the big issues with brain cancer treatments is how to get the drug to the tumor, because most drugs given intravenously cannot reach the brain. Therefore, we are developing GB13 to be administered directly into the brain tumor by a process called convection enhanced delivery (CED), which infuses a therapy over many hours with catheters. CED has been studied for many years, is safe for this kind of application, and limits toxicity compared to giving a drug through the blood stream. One of the limitations of CED is that many studies do not evaluate tumor distribution during infusion, which negatively impacts trial results and hinders clinical success. This is one recognized reason why CED-based therapies have failed despite there being preclinical steps that can be taken to answer this question. We are committed to performing the studies required to determine GB13 distribution to perform the most successful clinical trial possible. This proposal will address three main objectives. First, Targepeutics’ biologic therapy, GB13, will be labeled with a radioactive molecule to enable positron emission tomography (PET) imaging. Second, labeled GB13 will be administered to adult GBM and pediatric DMG animal tumors to determine the co-distribution with clinically validated magnetic resonance imaging (MRI) molecules. Finally, to address requirements for clinical trial approval, GB13 systemic distribution, and maximum dosing will be analyzed in animal models. Overall, successful completion of these studies will result in a phase 1 clinical trial application for GB13 treatment of adult GBM and pediatric DMG. We will learn how to visualize the distribution of GB13 that will be used in the clinic and is critical for understanding trial data. Although there are many clinical trials that use CED, none have been approved by the U.S. Food and Drug Administration. One of the main reasons is because the distribution is unclear. We hypothesize that the answers gained from this Department of Defense Impact Grant will positively impact thousands of brain cancer patients each year. Because we are incorporating studies needed for clinical trial approval, we will be prepared to enter clinical trials no later than the conclusion of this grant. This grant represents some of the last remaining tests before we can submit the phase 1 clinical trial design. The clinical applications of this proposal will directly impact the Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of brain cancer and pediatric brain tumors by directly providing information that is critical for successful delivery of GB13 to the brain. This application will address the Overarching Challenge category of Therapeutics and the critical gap of advancing immunotherapy across the different PRCRP Topic Areas. These studies will address the military health focus of environmental exposure risk factor associated with cancer, as there is a correlation identified in Veterans of the Gulf War, who are found to be at an increased risk for brain cancer and brain cancer related death due to nerve gas exposure in Iraq.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310681
Entities
People
- Randy Schrecengost
Organizations
- Mayo Clinic
- United States Army