Background: Adoptive T cell therapy targeting antigens expressed in glioblastoma multiforme (GBM) has emerged as potential therapeutic strategy to prevent or delay recurrence and prolong overall survival. Ephrin receptor A3 (EphA3), which is highly expressed on GBM; in particular, by the tumour vasculature and glioma stem cells is an ideal target for immune-based therapies.
Methods: We have designed an EphA3-taregting chimeric antigen receptor (CAR) using the single chain variable fragment of a novel monoclonal antibody and assessed its therapeutic potential against EphA3-expressing patient-derived glioma neurospheres, organoids and xenografted GBM tumours in immunodeficient mice.
Results: In vitro expanded allogeneic EphA3 CAR T cells form healthy individuals efficiently recognize and kill EphA3-positive GBM cells in vitro. Furthermore, these effector cells demonstrated curative efficacy in an orthotopic xenograft model of GBM. EphA3 CAR T cells were equally effective in targeting patient-derived neurospheres and infiltrate, desegregate, and kill GBM-derived organoids.
Conclusions: This study presents compelling evidence supporting the therapeutic potential of allogeneic EphA3-CAR T cell therapy against GBM. EphA3 is expressed in multiple tumour types, including colon, prostate, gastric, lung, kidney, and breast cancers. The ability to target EphA3-expressing cancer stem cells and the tumour vasculature in various tumours underscores the translational significance of EphA3-CAR T cell therapy in the quest for effective and targeted treatments.