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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
- Source :
- Cancer Gene Therapy. 22:487-495
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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.
- Subjects :
- Cancer Research
Immunological Synapses
Recombinant Fusion Proteins
T-Lymphocytes
medicine.medical_treatment
Receptors, Antigen, T-Cell
Mice, SCID
Biology
Immunotherapy, Adoptive
Cell therapy
Interferon-gamma
Immune system
Antigen
Mice, Inbred NOD
Cell Line, Tumor
medicine
Animals
Humans
Immunologic Factors
Epidermal growth factor receptor
Lenalidomide
Molecular Biology
Mice, Knockout
CD28
Glioma
Immunotherapy
Combined Modality Therapy
Xenograft Model Antitumor Assays
Molecular biology
Chimeric antigen receptor
Thalidomide
ErbB Receptors
Treatment Outcome
biology.protein
Molecular Medicine
Interleukin Receptor Common gamma Subunit
Single-Chain Antibodies
Subjects
Details
- ISSN :
- 14765500 and 09291903
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Cancer Gene Therapy
- Accession number :
- edsair.doi.dedup.....c9c7d1e6c2225dcb35b21fff74dc0176