Uncovering the intrinsic mechanisms of B7-H3 upregulation in Ewing sarcoma to enable next-generation CAR T cell therapy
Ewing sarcoma is a rare but deadly cancer that affects children and adolescents. It has a very poor prognosis and currently lacks effective treatment options. In recent years, a new type of therapy named “CAR T cells” has shown great results in several types of pediatric cancer. Briefly, CAR T cells are immune cells taken from the patient’s blood, then modified and “trained” outside the body to recognize and attack a specific protein (“the target”) that is overexpressed on the surface of cancer cells, with the goal of destroying the tumor once these modified cells are reinjected into the patient. This type of immunotherapy has found great success in certain pediatric blood cancers, but has limited success in treating solid tumors, mainly because few safe and specific targets exist. Luckily, a very promising target is B7-H3, highly overexpressed in many types of solid pediatric cancers, especially in Ewing sarcoma. Despite its great potential, nobody understands the biology behind B7-H3 overexpression, limiting our ability to design new immunotherapies that fully exploit its distinct biology. Thus, this project has two complementary aims: (1) to uncover the biological mechanisms that regulate B7-H3 expression in Ewing sarcoma cells, and (2) to engineer novel CAR T cell strategies that leverage its biology. Ultimately, this work will help us better understand B7-H3 biology in Ewing sarcoma and lead to the development of new effective therapies for this devastating disease.
Project Goals
Our goal is to generate new and effective treatment options for Ewing sarcoma by first (1) understanding the biological mechanisms that govern B7-H3 overexpression in this cancer and, second, (2) by exploiting these mechanisms to rationally engineer new CAR T cell variants that take advantage of B7-H3 biology while reducing on-target, off-tumor toxic effects. Our preliminary data suggest that B7-H3 expression is regulated by a specific cell-state program (“pro-mesenchymal program”) that remains active in Ewing sarcoma cells and may sustain high B7-H3 levels. Thus, our first aim is to confirm that B7-H3 is part of this program and to determine whether genetic or pharmacological perturbations can further boost its expression, enabling more effective CAR T cell therapies. Our second aim focuses on engineering next-generation CAR T cells that effectively target Ewing sarcoma cells, alone or in combination with the perturbations of B7-H3 regulators identified in Aim 1. We will test the new ZAP70-CAR T cells, developed in our laboratory, using patient-derived Ewing sarcoma tumors implanted in mouse models to evaluate their effectiveness when compared with current clinical CAR T cells, as well as their potential to avoid on-target, off-tumor toxicities. In conclusion, this project integrates basic and translational approaches to address Ewing sarcoma and to establish a foundation for expanding B7-H3-targeted therapies to other pediatric solid tumors.
