Retrovirally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen.
The isotype of epidermal growth factor receptor variant III (EGFRvIII) is often identified in glioblastomas. Previously, we created a mouse monoclonal antibody, 3C10 (IgG2b), that specifically recognized EGFRvIII, and a recombinant single-chain variable fragment of 3C10. The aim of the current study was to develop genetically engineered T cells, termed T-bodies, that express a chimeric receptor consisting of the 3C10 single-chain variable fragment coupled to signaling modules such as the CD3zeta (ζ) chain, for the treatment of tumors expressing mutant EGFR. After successful construction of the chimeric 3C10/CD3ζ T-cell receptor, its expression on the T-body was observed using western blotting and flow cytometry. The specificity of the T-body for EGFRvIII was evaluated using an interferon-gamma Elispot assay and a standard (51) Cr-release cytotoxicity assay. Furthermore, we demonstrated that the systemically delivered T-body infiltrated the intrabrain tumor and significantly delayed tumor growth. These results indicate that the T-body expressing the chimeric 3C10/CD3ζ T-cell receptor specifically recognized glioma cells expressing EGFRvIII. In conclusion, T-body-based immunotherapy appears to be a promising approach for the treatment of glioma.
Ohno
Masasuke
M
Department of Neurosurgery, Nagoya University School of Medicine, Nagoya Center for Cell Therapy, Aichi Medical University, Nagakute, Aichi, Japan.
Natsume
Atsushi
A
Ichiro Iwami
Ken
K
Iwamizu
Hidetaka
H
Noritake
Kana
K
Ito
Daiki
D
Toi
Yuki
Y
Ito
Motokazu
M
Motomura
Kazuya
K
Yoshida
Jun
J
Yoshikawa
Kazuhiro
K
Wakabayashi
Toshihiko
T
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D002469:Cell Separation; D058501:Enzyme-Linked Immunospot Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005434:Flow Cytometry; D005818:Genetic Engineering; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D057127:Single-Chain Antibodies / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; D057127:Single-Chain Antibodies; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors