Abstract
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.
Highlights
Glioblastoma is the most common and aggressive brain malignancy without effective treatment options [1, 2]
Humanized scFv recognizes overexpressed epidermal growth factor receptor (EGFR) and EGFRvIII in tumor cells To avoid anaphylaxis caused by mouse scFv-derived chimeric antigen receptor–engineered T (CAR T) cells [29], we generated a panel of humanized antibody fragments derived from a mouse EGFR monoclonal antibody 7B3 that bound EGFR287-302 (Supplementary Table S1; Supplementary Fig. S1)
The scFv derived from anti-EGFR antibody C225 and Monoclonal antibody 806 (mAb 806) were used as controls (Supplementary Fig. S3)
Summary
Glioblastoma is the most common and aggressive brain malignancy without effective treatment options [1, 2]. In the United States, approximately 10,000 new cases are diagnosed annually [3]. Standard-of-care procedures include surgical resection followed by radiotherapy and/or chemotherapy with the alkylating agent temozolomide [4]. The prognosis of glioblastoma remains very poor, with a median survival of less than 2 years [5]. The resistance of glioblastoma to standard therapies results in a high rate of tumor recurrence, and the lack of tumor specificity of the treatment may result in a significant damage to healthy brain tissues [6]. There is a high unmet medical need for a safe and efficacious tumor-selective therapy against glioblastoma
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