Epstein Barr virus-specific cytotoxic T lymphocytes expressing the anti-CD30ζ artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease

Barbara Savoldo, Cliona M. Rooney, Antonio Di Stasi, Hinrich Abken, Andreas Hombach, Aaron E. Foster, Lan Zhang, Helen E. Heslop, Malcolm K. Brenner, Gianpietro Dotti

Research output: Contribution to journalArticle

173 Scopus citations

Abstract

Adoptive transfer of Epstein Barr virus (EBV)-specific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV+ Hodgkin lymphoma (HD) to produce complete tumor responses. Treatment failure, however, occurs if a subpopulation of malignant cells in the tumor lacks or loses expression of EBV antigens. We have therefore determined whether we could prepare EBV-CTLs that retained the antitumor activity conferred by their native receptor while expressing a chimeric antigen receptor (CAR) specific for CD30, a molecule highly and consistently expressed on malignant Hodgkin Reed-Sternberg cells. We made a CD30CAR and were able to express it on 26% (± 11%) and 22% (± 5%) of EBV-CTLs generated from healthy donors and HD patients, respectively. These CD30CAR+ CTLs killed both autologous EBV+ cells through their native receptor and EBV -/ CD30+ targets through their major histocompatibility complex (MHC)-unrestricted CAR. A subpopulation of activated T cells also express CD30, but the CD30CAR+ CTLs did not impair cellular immune responses, probably because normal T cells express lower levels of the target antigen. In a xenograft model, CD30CAR+ EBV-CTLs could be costimulated by EBV-infected cells and produce antitumor effects even against EBV-/CD30+ tumors. EBV-CTLs expressing both a native and a chimeric antigen receptor may therefore have added value for treatment of HD.

Original languageEnglish (US)
Pages (from-to)2620-2630
Number of pages11
JournalBlood
Volume110
Issue number7
DOIs
StatePublished - Oct 1 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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