CAR T-cells Secreting BiCE Against DIPG

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain cancer that occurs in children. Despite decades of research, current treatments only temporarily slow the disease, and nearly all children with DIPG die within a year of diagnosis. One promising type of treatment uses the body’s own immune system to fight cancer. In this approach, immune cells called T-cells are taken from a patient, genetically reprogrammed in the laboratory to recognize cancer cells, and then returned to the patient to attack the tumor. These “CAR T-cells” have shown remarkable success in some blood cancers, but their effectiveness against solid tumors like DIPG has been limited. This is because gliomas often have a mix of different markers on their surface, and immune-suppressive cells within the tumor can block immune responses.

Our proposal aims to develop a smarter, safer immune therapy for DIPG by combining two complementary strategies. We will engineer T-cells that recognize a protein called B7-H3, which is found on DIPG cells. In addition, these T-cells will be programmed to release a second agent — a BiCE engager— that can attract and activate other immune cells, such as natural killer cells and brain-resident microglia, to target a second marker, GD2, on tumor cells. The idea is that the engineered T-cells will directly kill cancer cells they recognize, while the secreted engager will recruit additional immune help against tumor cells that might escape direct T-cell detection.

In the laboratory, we will first test whether these dual-function immune cells work against DIPG cells grown in culture. Next, we will evaluate their safety and effectiveness in mouse models that closely mimic human DIPG. Finally, we will study how these engineered T-cells change the immune environment within tumors, particularly whether they can reprogram the brain’s own immune cells to support a sustained anti-tumor response.