Efficacy of MET-targeting CAR T cells against glioblastoma patient-derived xenograft models

Background: Genetic alteration of the MET receptor tyrosine kinase frequently occurs in glioblastoma (GBM). Clinically, bevacizumab treatment results in MET signaling activation, leading to GBM recurrence with a more malignant phenotype. While MET has been a promising therapeutic target, MET inhibitors have not been successful in treating GBM patients. MET-directed chimeric antigen receptor (CAR) T cells hold the promise of targeting MET-positive GBM regardless of genetic alterations or kinase activity. Methods: GBM patient-derived xenografts (PDX) harboring MET amplification (MET^amp) or PTPRZ-MET fusion (ZM) were propagated in vivo followed by glioma stem cell (GSC) isolation. Cell-based assays were used for comparing GSC survival in response to MET inhibitors and CAR T cells. Multi-panel cytokine release was analyzed to profile MET-CAR T cell activation during co-culture with GBM. Orthotopic tumor growth and real-time imaging were performed to evaluate MET-CAR T cell therapeutic efficacy in vivo. Results: Although GBM are heterogeneous tumors, neuro-sphere cells isolated from MET^amp or ZM fusion PDX tumors showed universal cognate genetic MET alteration along with GSC markers such as SOX2 and nestin. Both MET^amp and ZM fusion tumors showed MET overexpression but only the MET^amp cells presented activated MET signaling which was vulnerable to MET inhibitors. In contrast, MET-CAR T cells specifically inhibited all MET-positive tumor growth regardless of MET activation status. Conclusions: Whereas MET inhibitors are effective in MET-active tumors, MET-CAR T cells eradicate MET-positive GBM growth in an antigen-dependent manner, demonstrating a promising therapeutic approach for treating MET-positive GBM. MET overexpression, especially MET^amp and ZM fusion may be used to predefine the GBM patients for treating with MET-CAR T cell therapy.