title: Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor.
abstract: Transforming growth factor (TGF)-beta is produced in most human tumors and markedly inhibits tumor antigen-specific cellular immunity, representing a major obstacle to the success of tumor immunotherapy. TGF-beta is produced in Epstein-Barr virus (EBV)-positive Hodgkin disease and non-Hodgkin lymphoma both by the tumor cells and by infiltrating T-regulatory cells and may contribute the escape of these tumors from infused EBV-specific T cells. To determine whether tumor antigen-specific cytotoxic T lymphocytes (CTLs) can be shielded from the inhibitory effects of tumor-derived TGF-beta, we previously used a hemagglutinin-tagged dominant negative TGF-betaRII expressed from a retrovirus vector to provide CTLs with resistance to the inhibitory effects of TGF-beta in vitro. We now show that human tumor antigen-specific CTLs can be engineered to resist the inhibitory effects of tumor-derived TGF-beta both in vitro and in vivo using a clinical grade retrovirus vector in which the dominant negative TGF-beta type II receptor (DNRII) was modified to remove the immunogenic hemagglutinin tag. TGF-beta-resistant CTL had a functional advantage over unmodified CTL in the presence of TGF-beta-secreting EBV-positive lymphoma, and had enhanced antitumor activity, supporting the potential value of this countermeasure.
authors.affiliation: Center for Cell and Gene Therapy, The Methodist Hospital and Texas Children's Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Foster
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: An
authors.initials: A
authors.lastname: Lu
authors.forename: Mariam
authors.initials: M
authors.lastname: Khalil
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005799:Genes, Dominant; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta