Targeting pediatric High-Grade Gliomas with OAcGD2-CAR Vδ2 T cells

Abstract

PurposePediatric high-grade gliomas (pHGG) belong to a family of rare childrens cancers which are treated with radiotherapy, based on adult high-grade glioma standard of care. However, new treatments are definitively required since actual ones are unable to extend survival by more than a few months in most patients. In this study, we investigate a Chimeric Antigen Receptor (CAR)-T cell immunotherapy targeting the OAcGD2 ganglioside, using either conventional {beta} or V{delta}2 T cells as effectors. Materials and methodsUsing relevant human primary models of pHGG, we first characterized the innate V{delta}2 T cell immunoreactivity. Then, following the validation of OAcGD2 expression in these tumor cells, we evaluated both {beta} and V{delta}2 OAcGD2-CAR-T cell immunoreactivity using various methods including videomicroscopy, FACS and cytotoxicity assays. ResultsWe showed that pHGG primary cells are not spontaneously recognized and killed by V{delta}2 T cells but significantly expressed the OAcGD2 ganglioside. Accordingly, both {beta} and V{delta}2 T cells engineered to express a CAR against the OAcGD2 efficiently killed pHGG cells in 2D and 3D models. Importantly, only V{delta}2 T cells transduced with the complete OAcGD2-CAR eliminated pHGG cells, in contrast to conventional {beta} CAR-T cells that killed tumor cells even in the absence of CAR expression, highlighting the allogeneic potential of V{delta}2 CAR-T cells. ConclusionOur study demonstrates the preclinical relevance of targeting OAcGD2 in pHGG using CAR-T cells. Furthermore, we also clearly demonstrate the clinical benefits of using V{delta}2 T cells as CAR effectors in allogeneic settings allowing an off-the-shelf immunotherapy.