Isoform-specific TNC-redirected T cell Therapy for DIPG
DIPG remains an incurable brain tumor since current therapies, including radiation and chemotherapy, cannot destroy all DIPGs cells. Immunotherapy holds the promise to improve outcomes for children with DIPG since immune cells kill tumor cells through different mechanisms than radiation and chemotherapy. Among different forms of immunotherapy, an immunotherapy consisting of immune cells known as T cells as garnered significant excitement. These T cells are engineered to express a chimeric antigen receptor (CAR), and the generated CAR T cells have the ability to seek out and kill tumor cells. While promising, several limitations of CAR T cell immunotherapy for DIPG need to be addressed before it will be successful. This includes identifying CAR targets expressed on DIPG and improving the effector function of CAR T cells in the DIPG setting. In our innovative project, we now propose to overcome these limitations.
The long-term goal of this project is to develop an effective CAR T cell therapy for DIPG. In our preliminary studies we have shown that DIPGs express a variant of molecule called tenascin. We believe that this molecule represents an ideal CAR target since its expression is linked to DIPG being a cancer. We have therefore generated a functional CAR prototype and propose in the first part of the grant to optimize our CAR. In second part of the grant, we then will conduct studies to further improve the anti-tumor activity of DIPG-specific CAR T cells by expressing receptors that promote the growth of CAR T cells once they have recognized DIPG cells. We will use cell culture studies and models that closely mimic DIPGs to evaluate the generated DIPG-specific CAR T cells. This project will be led by two investigators with complementary expertise in immunotherapy for pediatric brain tumors and T cell engineering. If successful, we are planning to develop a clinical study to evaluate our approach in children, who have DIPG, in the future.