Vivekanand Yadav, Ph.D.
Assistant Professor, Hematology/Oncology, Children’s Mercy Hospital

Diffuse intrinsic pontine gliomas (DIPGs) represent one of the most aggressive and lethal pediatric brain tumors, with a median survival of less than one year. Despite advances in treatment, the prognosis remains dire; 300-400 kids every year die from this devastating brain cancer. CAR T cell therapy is a cutting-edge cancer treatment that uses a patient’s own immune system to fight cancer. T-cells from a donor/patient are genetically modified in the laboratory to express chimeric antigen receptors (CARs) on their surface which are designed to recognize and bind to cancer cells, enabling them to kill the cancer cells more effectively. After modification, the CAR T-cells are expanded to large numbers and infused back into the patient, where they seek out and destroy cancer cells. While successful in certain hematologic malignancies, CAR T cell therapy faces significant challenges in solid tumors like DIPGs due to the immunosuppressive tumor microenvironment (TME). A major challenge is that the CAR T cells are inactivated upon reaching TME. Think of CAR T cells as “missiles” launched to target tumor cells. Tumor cells have developed an “anti-missile” system that expresses immune suppressive molecules such as CD73, TIM3, etc. on their surface, which inactivate the CAR T cell-mediated tumor cell killing.

CD73, an ecto-5′-nucleotidase, plays a critical role in this immunosuppression by generating adenosine, which inhibits T-cell activity. Given the strong immunosuppressive properties of adenosine and its high expression in brain tumors, adenosine may constitute a significant part of the immunological barrier, leading to the failure of CAR T cell therapy. The goal of our research is to investigate the contribution of CD73 in immunosuppressive TME of DIPG and evaluate the potential of CD73 inhibition to enhance the efficacy of GD2 or B7-H3 CAR T cell therapy. Most of the current preclinical testing of CAR-T therapy is typically performed in immune-deficient mouse tumor models, which often fail to predict the impact of the TME on CAR-T cell activation and exhaustion. For this study, we have developed a novel immune-competent mouse model of DIPG to explore the immunological changes upon CD73 inhibition and CAR T cell treatment.

This project targets CD73 to enhance CAR T cell therapy for DIPG, uses a novel immunocompetent mouse model to study the TME, and introduces bi-specific CAR T cells to address tumor antigen heterogeneity. These approaches promise to transform DIPG treatment and offer new hope for affected children and their families.