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Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses

Cancer Gene Therapy volumeΒ 22,Β pages 487–495 (2015)Cite this article

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Abstract

The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ΞΆ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3+ T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3+ T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

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Acknowledgements

This work was supported by a Grant-in Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (AN no. 23107010) and a Grant-in-Aid for Young Scientists B (MO no. 25861270). We would like to thank Mr Masamitsu Harada (Cellgene) for his constructive suggestions and Mr Yutaka Hattori (Keyence) for his technical assistance in immunofluorescence imaging.

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Authors and Affiliations

  1. Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Aichi, Japan

    S Kuramitsu,Β M Ohno,Β F Ohka,Β S Shiina,Β A Yamamichi,Β A Kato,Β K Tanahashi,Β K Motomura,Β G Kondo,Β M Kurimoto,Β T WakabayashiΒ &Β A Natsume

  2. Division of Neurosurgery, Koujunkai Daido Hospital, Nagoya, Aichi, Japan

    S Kuramitsu

  3. Division of Neurosurgery, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan

    M Ohno

  4. Division of Cancer Biology, Nagoya University School of Medicine, Nagoya, Aichi, Japan

    T Senga

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Kuramitsu, S., Ohno, M., Ohka, F. et al. Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses. Cancer Gene Ther 22, 487–495 (2015). https://doi.org/10.1038/cgt.2015.47

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