期刊
CANCER IMMUNOLOGY RESEARCH
卷 4, 期 3, 页码 259-268出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-15-0060
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [23107010]
- Japan Agency for Medical Research and development, AMED
- Basic Science and Platform Technology Program for Innovative Biological Medicine from AMED
- Regional Innovation Strategy Support Program from MEXT
- [25861270]
- Grants-in-Aid for Scientific Research [25861270] Funding Source: KAKEN
Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)-transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1-based single-chain variable fragment) with CD28, 4-1BB, and CD3 zeta intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM. (C) 2016 AACR.
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