Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor.
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.
Foster
Aaron E
AE
Center for Cell and Gene Therapy, The Methodist Hospital and Texas Children's Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Dotti
Gianpietro
G
Lu
An
A
Khalil
Mariam
M
Brenner
Malcolm K
MK
Heslop
Helen E
HE
Rooney
Cliona M
CM
Bollard
Catherine M
CM
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
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta