Effective Locoregional Delivery of mRNA CAR T Cells for Diffuse Intrinsic Pontine Glioma
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor that occurs in children and is universally fatal, killing most patients within 1 year. This proposal aims to cure these brain tumors with a new approach using the body’s immune system. 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. The goal of this project is to use CAR T cells to seek out a target called GD2, a sugar molecule that sits on the outside of DIPG 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. We will first explore if these CAR T cells will reach the tumor if delivered in the fluid surrounding the brain. We will then test these CAR T cells across a panel of models of DIPG that are an accurate representation of human disease, investigating the best method to deliver the CAR T cells into the brain. We will also compare our RNA CAR T cells directly against permanent CAR T cells made with DNA to evaluate safety and efficacy, as we design a clinical trial of this therapy for patients with DIPG. Dr. Jessica Foster will lead this work and is currently an instructor in the Division of Oncology at the Children’s Hospital of Philadelphia (CHOP) where she sees pediatric brain tumor patients and completes her research. This award will include mentorship and guidance from Dr. John Maris, a world-renowned physician-scientist at CHOP who has trained 25 scientists to successful careers. The proposed work will directly advance Dr. Foster’s career in the PRCRP FY20 topic areas of immunotherapy and pediatric brain tumors, as she will learn new scientific techniques in advanced imaging technology to monitor the CAR T cells, as well as how to create permanent CAR T cells. Through presentation of her work at conferences, attending seminars, and forging new collaborations, she will develop critical thinking skills to pursue her independent career in novel immune based therapies for pediatric patients with brain tumors. Our goal is to create optimal dosing strategies that will lead directly to clinical trials to help cure these devastating brain tumors in children. The CAR T cells developed in this project will be used specifically for DIPG, but can also be used in other GD2 positive tumors including medulloblastoma, neuroblastoma, and melanoma. This work will directly inform the way CAR T cells are delivered to patients and specific dosing and timing of CAR T cells to maximize both safety and efficient treatment. This work will have direct translation to a clinical trial, and also inform treatment designs for CAR T cell therapy in other brain tumors in both pediatrics and adults. As pediatric brain tumors are the leading cause of cancer death in pediatric patients, it is imperative we seek out novel strategies to cure tumors like DIPG. This work will support mission readiness by addressing a gap in treatment of pediatric brain tumors, which will have a profound effect on the health and well-being of active Service members, their families, and the general public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110221
Entities
People
- Jessica Foster
Organizations
- United States Army