TY - JOUR
T1 - Induction of human T lymphocyte cytotoxicity and inhibition of tumor growth by tumor-specific diabody-based molecules secreted from gene-modified bystander cells
AU - Blanco, Belén
AU - Holliger, Phillip
AU - Vile, Richard G.
AU - Álvarez-Vallina, Luis
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003/7/15
Y1 - 2003/7/15
N2 - Infiltrating T cells are found in many malignancies, but they appear to be mostly anergic and do not attack the tumor, presumably because of the absence of activation and/or costimulatory signals. We describe a strategy for cellular antitumor immunotherapy by the in situ production of soluble bifunctional Ab-based molecules that activate and retarget T cells to the tumor. We genetically modified cells to simultaneously secrete two bifunctional molecules, a bispecific diabody directed against the carcinoembryonic Ag (CEA) and the CD3ε chain of the TCR (αCEA × αCD3), and a fusion protein comprising the extracellular portion of B7-1 fused to a bivalent anti-CEA diabody (B7-αCEA). Together, αCEA × αCD3 and B7-αCEA proved potent at inducing the activation, proliferation, and survival of primary human T cells. When producer cells were cocultured with primary T cells and CEA+ cancer cells, αCEA × αCD3 and B7-αCEA acted in combination to activate and retarget T cell cytotoxicity and completely abrogate tumor growth in the coculture. Furthermore, the introduction of just a few such producer cells at the tumor site efficiently inhibited the growth of established human colon carcinoma xenografts. Despite a cumbersome generation process, the use of autologous gene-modified producer cells opens the way for a new diabody-based gene therapy strategy of cancer.
AB - Infiltrating T cells are found in many malignancies, but they appear to be mostly anergic and do not attack the tumor, presumably because of the absence of activation and/or costimulatory signals. We describe a strategy for cellular antitumor immunotherapy by the in situ production of soluble bifunctional Ab-based molecules that activate and retarget T cells to the tumor. We genetically modified cells to simultaneously secrete two bifunctional molecules, a bispecific diabody directed against the carcinoembryonic Ag (CEA) and the CD3ε chain of the TCR (αCEA × αCD3), and a fusion protein comprising the extracellular portion of B7-1 fused to a bivalent anti-CEA diabody (B7-αCEA). Together, αCEA × αCD3 and B7-αCEA proved potent at inducing the activation, proliferation, and survival of primary human T cells. When producer cells were cocultured with primary T cells and CEA+ cancer cells, αCEA × αCD3 and B7-αCEA acted in combination to activate and retarget T cell cytotoxicity and completely abrogate tumor growth in the coculture. Furthermore, the introduction of just a few such producer cells at the tumor site efficiently inhibited the growth of established human colon carcinoma xenografts. Despite a cumbersome generation process, the use of autologous gene-modified producer cells opens the way for a new diabody-based gene therapy strategy of cancer.
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U2 - 10.4049/jimmunol.171.2.1070
DO - 10.4049/jimmunol.171.2.1070
M3 - Article
C2 - 12847281
AN - SCOPUS:0038108811
SN - 0022-1767
VL - 171
SP - 1070
EP - 1077
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -