Selective Targeting of Glioblastoma with EGFRvIII/EGFR Bitargeted Chimeric Antigen Receptor T Cell.

The heterogeneous expression of EGFRvIII [variant III mutant of epidermal growth factor receptor (EGFR)] in glioblastoma has significant impact on the clinical response to the treatment of EGFRvIII-specific chimeric antigen receptor-engineered T (CAR T) cells. We hypothesized that CAR T cells that could target both EGFRvIII and the form of EGFR expressed on tumor cells, but not EGFR on normal cells, would greatly improve efficacy without inducing on-target, off-tumor toxicity. Therefore, we developed a humanized single-chain antibody, M27, with a single specificity that binds to an epitope found both on wild-type EGFR- and EGFRvIII-overexpressing tumor cells, but not EGFR-expressing normal cells, including primary keratinocytes, on which wild-type EGFR is highly expressed. M27-derived CAR T cells effectively lysed EGFRvIII- or EGFR-overexpressing tumor cells, but showed no observable toxicity on normal cells. Inclusion of the CD137 (4-1BB) costimulatory intracellular domain in the M27-28BBZ CAR provided CAR T cells with higher tumor lysis activity than when not included (as in the M27-28Z CAR). The growth of established EGFR- or EGFRvIII-overexpressing glioma xenografts was suppressed by M27-28BBZ CAR T cells as well. The growth of heterogeneic xenograft tumors, created by mixing EGFR- and EGFR-overexpressing glioblastoma cells, was also effectively inhibited by M27-28BBZ CAR T cells. The survival of mice in the orthotopic models was significantly prolonged after M27-28BBZ CAR T-cell infusion. These results suggested that tumor-selective, bitargeted anti-EGFR/EGFRvIII CAR T cells may be a promising modality for the treatment of patients with EGFR/EGFRvIII-overexpressing glioblastoma. Cancer Immunol Res; 6(11); 1314-26. ©2018 AACR.

Jiang H ，Gao H ，Kong J ，Song B ，Wang P ，Shi B ，Wang H ，Li Z ... -  《-》

Antitumor efficacy of chimeric antigen receptor T cells against EGFRvIII-expressing glioblastoma in C57BL/6 mice.

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematological tumors. However, many challenges remain in improving the efficacy of CAR T cells in solid tumors. The epidermal growth factor receptor variant III (EGFRvIII) is only expressed in tumors but barely found in normal tissues, making it a good target for CAR T therapy. It is reported that 31-64% of glioblastoma (GBM) patients are EGFRvIII positive. Here we report the robust antitumor activities of CAR T cells targeting EGFRvIII-expressing mouse GBM cells. In vitro and in vivo, 806-28Z CAR T cells were able to lyse GL261/EGFRvIII cellsin a dose-dependent manner. A low dose of 806-28Z CAR T cells suppressed GL261/EGFRvIII tumor growth, whereas a high dose of 806-28Z CAR T cells completely eradicated xenograft tumors. Higher concentrations of granzyme B in mice plasma were correlated with increased CAR T cells infusion. Enhanced CD8+ T cells infiltration within the tumors were detected by immunohistochemistry in sections from the mice treated by CAR T cells. The 806-28Z CAR T cells can also inhibit the growth of antigenic heterogeneous GBM tumors. More importantly, additional rechallenge experiments indicated that GL261/EGFRvIII cells or parental GL261 cells could not grow in the cured mice. Therefore, the cell dose is a crucial determinant for CAR T efficacy against EGFRvIII-expressing GBM and granzyme B release is a predictive marker for the antitumor efficacy of CAR T cells.

Chen M ，Sun R ，Shi B ，Wang Y ，Di S ，Luo H ，Sun Y ，Li Z ，Zhou M ，Jiang H ... -  《-》

CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells.

Han J ，Chu J ，Keung Chan W ，Zhang J ，Wang Y ，Cohen JB ，Victor A ，Meisen WH ，Kim SH ，Grandi P ，Wang QE ，He X ，Nakano I ，Chiocca EA ，Glorioso Iii JC ，Kaur B ，Caligiuri MA ，Yu J ... -  《Scientific Reports》

Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy.

Zhang Z ，Jiang J ，Wu X ，Zhang M ，Luo D ，Zhang R ，Li S ，He Y ，Bian H ，Chen Z ... -  《-》

Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma.

Sahin A ，Sanchez C ，Bullain S ，Waterman P ，Weissleder R ，Carter BS ... -  《PLoS One》