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Transduction of cytotoxic T lymphocytes may be safe for cancer treatment

07-07-2006

A study from the United States has reported on the safety assessment of cytotoxic T lymphocytes (CTLs) transduced with a dominant negative transforming growth factor (TGF)-beta receptor (DNR).

"TGF-beta, a pleiotropic cytokine that regulates cell growth. is secreted by many human tumors and markedly inhibits tumor-specific cellular immunity. It has previously been shown by our group that transduction of CTLs with a retroviral vector expressing the DNR overcomes this tumor evasion in a model of Epstein-Barr virus (EBV)-positive Hodgkin disease," wrote K. Lacuesta and colleagues, Baylor College of Medicine.

They continued, "TGF beta is an important physiologic regulator of T-cell growth and survival, however, abrogation of this regulatory signal in genetically modified cells is potentially problematic. To ensure that unresponsiveness to TGF beta did not lead to the unregulated growth of genetically modified CTLs, the characteristics of DNR-transduced CTLs in vivo were studied."

"Donor C57BL6 mice were vaccinated with human papillomavirus-E7 plasmid DNA to induce production of E7-specific CTLs. The E7-specific CTLs were genetically modified to express enhanced green fluorescent protein (GFP) or DNR and administered to syngeneic mice. All mice received monthly boosts with E7 DNA for 9 months, and during this time, transduced CTLs were detected in the peripheral blood of most of the mice using a quantitative real-time polymerase chain reaction.

"By 12 months, 3 months after cessation of vaccination, no DNR-transduced CTLs or GFP-transduced CTLs were detected in the peripheral blood. There were 4 cases of lymphoma (2 DNR-transduced mice and 2 control mice): all tumors were CD3-/CD8- and were also negative for the DNR transgene," the authors reported.

"Hence," concluded the scientists, "mature antigen-specific cytotoxic T cells can be genetically modified to resist the antiproliferative effects of TGF beta without undergoing spontaneous lymphoproliferation in vivo. They may be of value for treating human cancers, which use TGF beta as a powerful immune evasion mechanism."

Lacuesta and colleagues published their study in the Journal of Immunotherapy (Assessing the safety of cytotoxic T lymphocytes transduced with a dominant negative transforming growth factor-beta receptor. J Immunother, 2006;29(3):250-260).

For more information, contact C.M. Bollard, Baylor College of Medicine, Center Cell & Gene Therapy, 1 Baylor Plaza, Houston, TX 77030, USA.

Publisher contact information for the Journal of Immunotherapy is: Lippincott Williams & Wilkins, 530 Walnut St., Philadelphia, PA 19106-3621, USA.

Keywords: Houston, Texas, United States, Biological Therapy, DNA Research, Epstein-Barr Virus, Immunotherapy, Lymphoproliferation, Transgenes, Transforming Growth Factor Beta, T Lymphocyte.

This article was prepared by Cancer Gene Therapy Week editors from staff and other reports. Copyright 2006, Cancer Gene Therapy Week via NewsRx.com.