TY - JOUR
T1 - Assessing the safety of cytotoxic T lymphocytes transduced with a dominant negative transforming growth factor-β receptor
AU - Lacuesta, Kristine
AU - Buza, Elizabeth
AU - Hauser, Hans
AU - Granville, Laura
AU - Pule, Martin
AU - Corboy, Greg
AU - Finegold, Milton
AU - Weiss, Heidi
AU - Chen, Si Y.
AU - Brenner, Malcolm
AU - Heslop, Helen
AU - Rooney, Cliona M.
AU - Bollard, Catherine M.
PY - 2006/5
Y1 - 2006/5
N2 - Transforming growth factor (TGF)-β, 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 cytotoxic T lymphocytes (CTLs) with a retroviral vector expressing the dominant-negative TGFβ type II receptor (DNR) overcomes this tumor evasion in a model of Epstein-Barr virus (EBV)-positive Hodgkin disease. TGFβ 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 TGFβ 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. Hence, mature antigen-specific cytotoxic T cells can be genetically modified to resist the antiproliferative effects of TGFβ without undergoing spontaneous lymphoproliferation in vivo. They may be of value for treating human cancers, which use TGFβ as a powerful immune evasion mechanism.
AB - Transforming growth factor (TGF)-β, 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 cytotoxic T lymphocytes (CTLs) with a retroviral vector expressing the dominant-negative TGFβ type II receptor (DNR) overcomes this tumor evasion in a model of Epstein-Barr virus (EBV)-positive Hodgkin disease. TGFβ 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 TGFβ 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. Hence, mature antigen-specific cytotoxic T cells can be genetically modified to resist the antiproliferative effects of TGFβ without undergoing spontaneous lymphoproliferation in vivo. They may be of value for treating human cancers, which use TGFβ as a powerful immune evasion mechanism.
KW - Lymphoma
KW - Safety
KW - Transforming Growth Factor-beta
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U2 - 10.1097/01.cji.0000192104.24583.ca
DO - 10.1097/01.cji.0000192104.24583.ca
M3 - Article
C2 - 16699368
AN - SCOPUS:33746068320
VL - 29
SP - 250
EP - 260
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
SN - 1524-9557
IS - 3
ER -