Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors

• DOI: 10.1136/jitc-2021-004450
• Publication Date: 2022-09-27T16:52:08Z
• Authors: Jessica B Foster; Crystal Griffin; Jo Lynne Rokita; Allison Stern; Cameron Brimley; Komal Rathi; Maria V Lane; Samantha N Buonge...; Tiffany Smith; Peter J Madsen; Daniel Martinez; Alberto Delaidelli; Poul H Sorensen; Robert J Wechsler...; Katalin Karikó; Phillip B Storm; David M Barrett; Adam C Resnick; John M Maris; Kristopher R Bosse
• Keywords: Pediatric cancer; Brain tumor

Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed neuroblastoma which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression pediatric and develop mRNA CAR T approach against this target.We investigated across cohort primary tumor samples lines using RNA sequencing, immunohistochemistry, flow cytometry. To target adoptive cellular therapies mitigate potential inflammatory neurotoxicity, we used optimized create transient chimeric antigen receptor (CAR) cells. We developed four constructs highly GPC2-specific fully human D3 single chain variable fragment preclinical testing.We identified high multiple types including medulloblastomas, embryonal multilayered rosettes, other central nervous system tumors, as well definable subsets malignant gliomas. next validated prioritized configurations vitro cytotoxicity assays GPC2-expressing cells, where light-to-heavy proved be superior. expanded testing two most potent GPC2-directed medulloblastoma high-grade glioma lines, showing significant models. Finally, biweekly locoregional delivery 2-4 million cells induced regression orthotopic model significantly prolonged survival aggressive thalamic diffuse midline xenograft model. No related neurologic or systemic toxicity was observed.Taken together, these data show that differentially protein on can safely local laying framework clinical translation tumors.