Exploiting glypican diversity in neuroblastoma plasticity with bicistronic CAR T cell targeting
Neuroblastoma is an aggressive cancer of the developing nerves that occurs in young children. There has been little improvement in the prognosis of children diagnosed with high-risk neuroblastoma over the last few decades. Recent advances in the field of cancer immunotherapy (using the immune system to combat tumors) have resulted in unheralded enthusiasm for the use of this potent treatment to fight against neuroblastoma. However, we desperately need new molecules and novel approaches to safely and most effectively target neuroblastoma cells with the immune system. We have recently discovered that the molecule glypican 2 (GPC2) is selectively found on the neuroblastoma tumor cell surface (but not on most normal cells), that GPC2 helps neuroblastomas and other tumors grow, and that GPC2 may also act as a signal to attract genetically modified immune cells (T cells), called chimeric antigen receptor (CAR) T cells, to the tumor to treat it. However, rare neuroblastoma tumor cells don?t have GPC2 on their surface making them resistant to this therapy. Conversely, these rare tumor cells contain a similar but different molecule called glypican 3 (GPC3). Thus, a CAR T cell that recognizes both GPC2 and GPC3 may provide a more effective and long-lasting immunotherapy for children with neuroblastoma.
An ALSF A award allows us to address the difficult challenge of using chimeric antigen receptor (CAR) T cells to treat pediatric solid tumors. We will overcome the immunotherapeutic hurdles of antigen loss and phenotypic plasticity in the lethal pediatric tumor neuroblastoma by utilizing a new dual antigen CAR T cell targeting approach. This award allows us to generate a team of scientists with complementary expertise specifically focused on this challenging project with an overall goal of developing a transformative new therapy for children with this relentless pediatric solid tumor.