CAR T cells targeting Podoplanin reduce orthotopic glioblastomas in mouse brains

Satoshi Shiina, Masasuke Ohno, Fumiharu Ohka, Shunichiro Kuramitsu, Akane Yamamichi, Akira Kato, Kazuya Motomura, Kuniaki Tanahashi, Takashi Yamamoto, Reiko Watanabe, Ichiro Ito, Takeshi Senga, Michinari Hamaguchi, Toshihiko Wakabayashi, Mika K. Kaneko, Yukinari Kato, Vidyalakshmi Chandramohan, Darell D. Bigner, Atsushi Natsume

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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 CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CART 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.

Original languageEnglish
Pages (from-to)259-268
Number of pages10
JournalCancer Immunology Research
Volume4
Issue number3
DOIs
Publication statusPublished - 2016 Mar

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Shiina, S., Ohno, M., Ohka, F., Kuramitsu, S., Yamamichi, A., Kato, A., Motomura, K., Tanahashi, K., Yamamoto, T., Watanabe, R., Ito, I., Senga, T., Hamaguchi, M., Wakabayashi, T., Kaneko, M. K., Kato, Y., Chandramohan, V., Bigner, D. D., & Natsume, A. (2016). CAR T cells targeting Podoplanin reduce orthotopic glioblastomas in mouse brains. Cancer Immunology Research, 4(3), 259-268. https://doi.org/10.1158/2326-6066.CIR-15-0060