title: Gene-engineered varicella-zoster virus reactive CD4+ cytotoxic T cells exert tumor-specific effector function.
abstract: T cells with grafted specificities for surface antigens provide an avenue for rapidly producing immune effector cells with tumor specificity. However, the function of chimeric receptor (chRec) gene-modified T cells is limited by lack of T-cell expansion and persistence. We propose to use varicella zoster virus (VZV)-reactive T cells as host for the chRec because these cells can be expanded both in vitro and in vivo by stimulation of their native receptor during endogenous reexposure to the virus or by administration of VZV vaccine. We obtained human T cells reactive with VZV from the peripheral blood of seropositive donors by stimulation with VZV lysate and evaluated their characteristics after genetic modification with two tumor-specific model chRecs. Cultures dominated by cytolytic CD4(+) T cells (VZV-CTL) could be expanded and maintained in vitro. Gene-modified VZV-CTL recognized and lysed tumor targets in a MHC-independent manner while maintaining functional, MHC-restricted interaction with VZV antigen through their native receptor. Thus, chRec-transduced VZV-CTL may provide a source of potent tumor-reactive cells for adoptive immunotherapy of cancer. The availability of a safe and effective VZV vaccine provides the option of repeated in vivo stimulation to maintain high T-cell numbers until the tumor is eliminated.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Landmeier
authors.forename: Bianca
authors.initials: B
authors.lastname: Altvater
authors.forename: Sibylle
authors.initials: S
authors.lastname: Pscherer
authors.forename: Bodo R
authors.initials: BR
authors.lastname: Eing
authors.forename: Joachim
authors.initials: J
authors.lastname: Kuehn
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Heribert
authors.initials: H
authors.lastname: Juergens
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossig
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D014645:Herpesvirus 3, Human / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D030781:Organisms, Genetically Modified / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013379:Substrate Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014161:Transduction, Genetic