New Investigator Grant Awarded to Giedre Krenciute

The intent of this project is to develop antigen-specific T cells as an effective immunotherapy for diffuse intrinsic pontine glioma (DIPG), a devastating pediatric brain tumor that is largely resistant to radiation and chemotherapy, resulting in dismal outcomes. The body’s native immune defenses against cancer often fail because the cancer either does not provoke or actively inhibits immune responses. However, genetic modification of the patient’s own immune system can be used to endow T cells with improved ability to recognize and kill cancerous cells that would not otherwise respond to conventional therapies. Cancer treatments consisting of the infusion of T cells that are engineered to recognize tumor antigens, molecules present only on cancers cells, have shown dramatic success in clinical studies against leukemia. We have now developed such an approach for pediatric patients with DIPG. In our method, we target a molecule called B7-H3, which is present on DIPG cells. We have genetically modified T cells to kill tumor cells expressing B7-H3 and have shown that they have anti-DIPG activity in pre-clinical studies. In this project, we now propose to improve our B7-H3-targeted approach for DIPG. In Aim 1 we will test if elimination of molecules that restrict T cell division and killing activity can further improve T cell anti-DIPG activity. In Aim2 we will examine and characterize the effect of the DIPG microenvironment on T cell activity. If our pre-clinical approach is successful and a clinical study is justified, we have the resources to develop a Phase I clinical trial at our institution.