Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor related deaths in pediatric cancers. DIPG is completely lethal, and palliative radiation therapy (RT) to control symptoms is currently the standard-of-care treatment for DIPG, therefore effective treatment is urgently needed. In recent phase 1 clinical trials, the promising potential for using chimeric antigen receptor T cell immunotherapy against the disialoganglioside GD2 (GD2-CART) has been established, where 75% of patients exhibited clinical and radiographic improvement. There has also been emerging evidence advocating for the combined use of GD2-CART therapy with conventional radiation (CONV-RT) to enhance the immune response in other solid brain tumors. Ultra-high dose rate radiotherapy, abbreviated as FLASH-RT, is an emerging radiation technique shown to reduce normal brain tissue damage while preserving tumor control, as compared to CONV-RT. It is currently unknown how FLASH-RT will affect CART therapy. We hypothesize that effective treatment for DIPG can be achieved by combining FLASH-RT with GD2-CART immunotherapy. We have shown FLASH-RT to equivocally kill DIPG cells as well as the standard-of-care, CONV-RT; Given the neurological tissue sparing effects of FLASH-RT, this radiotherapy alone could be an improvement for DIPG treatment. Additionally, we have validated that GD2 is highly expressed in our DIPG cell line, suggesting high GD2-CART target specificity. Additionally, we have found that GD2 expression on DIPG tumor cells remains unchanged upon treatment with FLASH-RT. Therefore, we can utilize FLASH-RT to target GD2 CART while sparing normal tissue and minimizing neurotoxicity, allowing for a promising avenue of combination treatment for this devastating pediatric cancer.