Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-β receptor

Aaron E. Foster, Gianpietro Dotti, An Lu, Mariam Khalil, Malcolm Brenner, Helen Heslop, Cliona M. Rooney, Catherine M. Bollard

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

Transforming growth factor (TGF)-β 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-β 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-β, we previously used a hemagglutinin-tagged dominant negative TGF-βRII expressed from a retrovirus vector to provide CTLs with resistance to the inhibitory effects of TGF-β in vitro. We now show that human tumor antigen-specific CTLs can be engineered to resist the inhibitory effects of tumor-derived TGF-β both in vitro and in vivo using a clinical grade retrovirus vector in which the dominant negative TGF-β type II receptor (DNRII) was modified to remove the immunogenic hemagglutinin tag. TGF-β-resistant CTL had a functional advantage over unmodified CTL in the presence of TGF-β-secreting EBV-positive lymphoma, and had enhanced antitumor activity, supporting the potential value of this countermeasure.

Original languageEnglish (US)
Pages (from-to)500-505
Number of pages6
JournalJournal of Immunotherapy
Volume31
Issue number5
DOIs
StatePublished - Jun 2008

Keywords

  • Cytotoxic T lymphocyte
  • Hodgkin disease
  • Non-Hodgkin lymphoma
  • TGF-b

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

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