Multiplex Engineered Gamma Delta CAR T Cell Therapy for DIPG
Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal pediatric brain cancer with no effective treatments, and most children survive less than a year after diagnosis. Chimeric Antigen Receptor (CAR) T cell therapy shows promise but struggles with brain tumor penetration, persistence, and immune suppression. This project focuses on gamma delta (?d) T cells, a rare immune cell type that naturally resists exhaustion, functions in the brain, and can kill cancer cells without traditional immune system signals. To enhance their effectiveness, we will use cutting-edge techniques to make multiple edits to the DNA of gd T cells. By disabling genes that suppress immune activity and shortening cell lifespan, we aim to improve tumor-killing ability and persistence. These engineered cells will also express a B7-H3 CAR, a receptor designed to specifically target DIPG cells. Additionally, we will test a “dual-CAR” strategy targeting both B7-H3 and GD2, two proteins found on DIPG cells. This approach increases the likelihood of recognizing and destroying all tumor cells while reducing their ability to evade the immune system. This study could revolutionize DIPG treatment by creating an off-the-shelf ?d T cell therapy, eliminating the need for patient-specific engineering. With expertise from St. Jude Children’s Research Hospital and the University of Minnesota, this project could rapidly advance to clinical trials, offering new hope for children with DIPG.
Project Goals
Diffuse Intrinsic Pontine Glioma (DIPG) is a deadly pediatric brain tumor with no effective treatments and a survival rate of less than a year. While chimeric antigen receptor (CAR) T cell therapy has shown promise for cancer treatment, it faces major challenges in DIPG, including poor persistence and suppression by the tumor environment. Our project seeks to develop a new type of immunotherapy using gamma delta (?d) T cells, a unique type of immune cell that can recognize and attack tumors without the limitations of conventional T cells. We will enhance ?d T cells using advanced genome engineering techniques. First, we will use gene-editing technology to improve their ability to survive, persist, and resist immune suppression. Next, we will design ?d T cells to target two key tumor markers, B7-H3 and GD2, increasing their ability to recognize and kill DIPG cells while reducing the risk of treatment resistance. Our approach also allows for an “off-the-shelf” therapy, eliminating the need for patient-specific manufacturing. By integrating these cutting-edge strategies, we aim to create a safe and effective immunotherapy that overcomes current limitations. This project will generate critical preclinical data needed for clinical trials, offering new hope for children with DIPG and advancing the broader field of cancer immunotherapy.
