Game Changer Grant Awarded to Robbie Majzner

The proposal builds on our experience treating children with diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) with GD2 chimeric antigen receptor (CAR) T cells. Several patients have developed significant responses, including one patient with a complete response that has been maintained for over a year. However, many patients showed only temporary improvement, and several did not respond at all. We have identified two key factors that hindered the success GD2 CAR T cells: the CAR T cells did not persist in the body for more than a month, and some tumors produced a protein that is able to suppress T cell activity.

In our first aim, we will test and validate a new type of GD2 CAR T cell that is capable of enhanced persistenceand anti-tumor efficacy. We have designed a unique signaling backbone that will allow GD2 CAR T cells to last longer, improving their ability to kill tumor cells. Our second aim focuses on subverting the tumors ability to secrete TGF-beta, a protein that tumors produce to stop CAR T cells from killing. We will design GD2 CAR T cells that are immune to the negative effects of TGF-beta, which will enhance their survival and activity within the highly immunosuppressive tumor.

In conclusion, this proposal aims to develop effective treatment options for children and young adults affected by DIPG/DMG. By leveraging findings from our clinical trial, we have identified obstacles that we can overcome by designing next-generation GD2 CAR T cells. These improved GD2 CAR T cells will provide a more effective therapeutic strategy for treating patients with DIPG/DMG.