Antitumor Activity of EBV-specific T Lymphocytes Transduced ... : Journal of Immunotherapy (original) (raw)

Basic Studies

Antitumor Activity of EBV-specific T Lymphocytes Transduced With a Dominant Negative TGF-β Receptor

Foster, Aaron E.* †; Dotti, Gianpietro* ‡; Lu, An*; Khalil, Mariam*; Brenner, Malcolm K.* † ‡; Heslop, Helen E.* † ‡; Rooney, Cliona M.* † § ∥; Bollard, Catherine M.* † ‡ §

*Center for Cell and Gene Therapy, The Methodist Hospital and Texas Children's Hospital

Departments of †Pediatrics

‡Medicine

§Immunology

∥Virology, Baylor College of Medicine, Houston, TX

Supported by NIH grant PO1 CA94237 and the GCRC at Baylor College of Medicine (RR00188), a Specialized Center of Research Award from the Leukemia Lymphoma Society, and a Doris Duke Distinguished Clinical Scientist Award to Helen E. Heslop, the Leukemia Lymphoma Society, awards from the Gillson Longenbaugh Foundation and the Carl C. Anderson Sr and Marie Jo Anderson Charitable Foundation and a Kimmel Translational Science Award (C.M.B.).

Financial Disclosure: The authors have declared there are no financial conflicts of interest in regard to this work.

Reprints: Catherine M. Bollard, Department of Pediatrics, Baylor College of Medicine, Houston, TX (e-mail: [email protected]).

Received for publication February 19, 2008; accepted March 22, 2008

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.