4.4 Article

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

Journal

JOURNAL OF IMMUNOTHERAPY
Volume 31, Issue 5, Pages 500-505

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e318177092b

Keywords

non-Hodgkin lymphoma; Hodgkin disease; TGF-beta; cytotoxic T lymphocyte

Funding

  1. NCI NIH HHS [P01 CA094237-06, P50 CA126752, P50 CA126752-03, P01 CA 94237, P01 CA094237] Funding Source: Medline
  2. NCRR NIH HHS [M01 RR000188, K01 RR000188, RR 00188] Funding Source: Medline

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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-beta RII 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.

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