Clinical translation of mRNA GD2-directed CAR T cells for diffuse midline glioma
Pediatric brain and spinal cord tumors are the deadliest form of childhood cancer. Diffuse midline glioma (DMG) stands out among these tumors as a particularly devastating disease that arises in the center of the brain at a median age of 6 years old. These central areas of the brain are important for our basic functions, so tumors in these locations cannot be surgically removed. Unfortunately, despite decades of clinical trials with radiation and chemotherapy, we have made little to no progress for patients with DMG. This tumor remains universally fatal with a median overall survival of around 1 year. With such aggressive tumors affecting often very young children, the cumulative years lost is substantial. With this in mind, new approaches that can affect outcomes for these patients have the potential to extend lives and have an immense impact on the families of these children and the community around them. Novel therapeutics are needed, and we believe using the immune system is an exciting new way to attack these tumors. Chimeric antigen receptor or “CAR” T cells are an immune-based cancer treatment that involves taking white blood cells from a patient, reprogramming them to seek out and attack tumor cells, then reintroducing these cells back into the patient where they destroy the cancer. Early clinical trials using CAR T cells are showing promise for brain tumors, and we hope to create safer and more effective CAR T cells for DMG.
Project Goals
Our work aims to bring an innovative treatment, RNA-based CAR T cell therapy, to children with DMG as we set out to translate our laboratory findings to clinical trial. We are using CAR T cells to seek out a target called GD2, a sugar molecule that sits on the outside of DMG tumor cells. This project is unique because we are using RNA to create the CAR T cells, which means the CAR T cells will be temporary and can be dosed like a drug, allowing for maximal safety. In addition, we will give the first dose of CAR T cells directly into the tumor, helping to maximize the CAR T cells that are recruited to the tumor. Aim 1 of this grant focuses on developing the necessary protocols to create clinical trial quality RNA-based CAR T cells, with all the testing that is necessary to fulfill FDA regulations. Aim 2 of this grant will ensure we have the background data needed to treat patients with the first dose of CAR T cells directly into the tumor, including the neurosurgical plan for how to administer. Together these aims will provide the backbone for the application that must be submitted to start a new clinical trial, which we aim to open at the end of this grant. This phase of translational research is often the most impactful, as it lays the foundation for the successful launch of a clinical trial. We hope our RNA based CAR T cells will improve the survival of children with these untreatable tumors and give hope to families and their children with this devastating diagnosis.
