title: Engineering NK Cells Modified With an EGFRvIII-specific Chimeric Antigen Receptor to Overexpress CXCR4 Improves Immunotherapy of CXCL12/SDF-1α-secreting Glioblastoma.
abstract: Natural killer (NK) cells are promising effector cells for adjuvant immunotherapy of cancer. So far, several preclinical studies have shown the feasibility of gene-engineered NK cells, which upon expression of chimeric antigen receptors (CARs) are redirected to otherwise NK cell-resistant tumors. Yet, we reasoned that the efficiency of an immunotherapy using CAR-modified NK cells critically relies on efficient migration to the tumor site and might be improved by the engraftment of a receptor specific for a chemokine released by the tumor. On the basis of the DNAX-activation protein 12 (DAP12), a signaling adapter molecule involved in signal transduction of activating NK cell receptors, we constructed an epidermal growth factor variant III (EGFRvIII)-CAR, designated MR1.1-DAP12 which confers specific cytotoxicity of NK cell towards EGFRvIII glioblastoma cells in vitro and to established subcutaneous U87-MG tumor xenografts. So far, infusion of NK cells with expression of MR1.1-DAP12 caused a moderate but significantly delayed tumor growth and increased median survival time when compared with NK cells transduced with an ITAM-defective CAR. Notably, the further genetic engineering of these EGFRvIII-specific NK cells with the chemokine receptor CXCR4 conferred a specific chemotaxis to CXCL12/SDF-1α secreting U87-MG glioblastoma cells. Moreover, the administration of such NK cells resulted in complete tumor remission in a number of mice and a significantly increased survival when compared with the treatment of xenografts with NK cells expressing only the EGFRvIII-specific CAR or mock control. We conclude that chemokine receptor-engineered NK cells with concomitant expression of a tumor-specific CAR are a promising tool to improve adoptive tumor immunotherapy.
authors.affiliation: *Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology, University Hospital Carl Gustav Carus ‡Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden §German Cancer Consortium (DKTK), Dresden †Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ∥Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Nadja
authors.initials: N
authors.lastname: Müller
authors.forename: Susanne
authors.initials: S
authors.lastname: Michen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Tietze
authors.forename: Katrin
authors.initials: K
authors.lastname: Töpfer
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulte
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.forename: Marc
authors.initials: M
authors.lastname: Schmitz
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Achim
authors.initials: A
authors.lastname: Temme
mesh_terms: D000818:Animals; D002460:Cell Line; D064987:Cell- and Tissue-Based Therapy; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D000066630:Ectopic Gene Expression; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005909:Glioblastoma / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D054377:Chemokine CXCL12; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors