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 do not 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.
Project Goal:
Neuroblastoma tumors contain different types of cells that can lead to immunotherapy resistance. This project will first focus on characterizing how these different neuroblastoma cells vary in the abundance of the molecules GPC2 or GPC3 on their surface, and how these GPC2 and GPC3 levels may change during the growth of the tumor or when treatment is applied to the tumor. We will also engineer next-generation GPC2.GPC3 CAR T cells that are able to home in on either GPC2 or GPC3 molecules on tumor cells to efficiently seek out all the different types of neuroblastoma cells and induce long-lasting tumor regression. We anticipate that findings from this research will have wide-spanning implications in how we design these types of immunotherapies for pediatric solid tumors in general and the role of these GPC2 and GPC3 molecules in both neuroblastoma tumor growth and resistance to cancer therapy.
Project Update 2025:
One of the challenges with treating neuroblastoma is that neuroblastoma tumors contain different types of cells which leads to treatment resistance. The project investigated how these different types of cells vary in the amount of GPC2 or GPC3 molecules they contain and furthermore, how these differences impact the tumor's reaction to treatment. We also worked with CAR T cells that are able to specifically interact with a certain type of neuroblastoma cell in order to inhibit the tumor's growth permanently. This project and future work that is yet to be done has broad implications in the field of neuroblastomas and pediatric solid tumors in general.
