2023 Game Changer Grant

Co-funded by Violet Foundation for pediatric brain cancer, SoSo Strong Pediatric Brain Tumor Foundation

Robbie Majzner, Recipient

Dana Farber Cancer Institute

Engineering Enhanced GD2 CAR T-Cells to Overcome DIPG Immune Resistance

Abstract:

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.