Adoptive transfer of gene-modified primary NK cells can specifically inhibit tumor progression in vivo
HJ Pegram, JT Jackson, MJ Smyth… - the Journal of …, 2008 - journals.aai.org
the Journal of Immunology, 2008•journals.aai.org
NK cells hold great potential for improving the immunotherapy of cancer. Nevertheless,
tumor cells can effectively escape NK cell-mediated apoptosis through interaction of MHC
molecules with NK cell inhibitory receptors. Thus, to harness NK cell effector function against
tumors, we used Amaxa gene transfer technology to gene-modify primary mouse NK cells
with a chimeric single-chain variable fragment (scFv) receptor specific for the human erbB2
tumor-associated Ag. The chimeric receptor was composed of the extracellular scFv anti …
tumor cells can effectively escape NK cell-mediated apoptosis through interaction of MHC
molecules with NK cell inhibitory receptors. Thus, to harness NK cell effector function against
tumors, we used Amaxa gene transfer technology to gene-modify primary mouse NK cells
with a chimeric single-chain variable fragment (scFv) receptor specific for the human erbB2
tumor-associated Ag. The chimeric receptor was composed of the extracellular scFv anti …
Abstract
NK cells hold great potential for improving the immunotherapy of cancer. Nevertheless, tumor cells can effectively escape NK cell-mediated apoptosis through interaction of MHC molecules with NK cell inhibitory receptors. Thus, to harness NK cell effector function against tumors, we used Amaxa gene transfer technology to gene-modify primary mouse NK cells with a chimeric single-chain variable fragment (scFv) receptor specific for the human erbB2 tumor-associated Ag. The chimeric receptor was composed of the extracellular scFv anti-erbB2 Ab linked to the transmembrane and cytoplasmic CD28 and TCR-ζ signaling domains (scFv-CD28-ζ). In this study we demonstrated that mouse NK cells gene-modified with this chimera could specifically mediate enhanced killing of an erbB2+ MHC class I+ lymphoma in a perforin-dependent manner. Expression of the chimera did not interfere with NK cell-mediated cytotoxicity mediated by endogenous NK receptors. Furthermore, adoptive transfer of gene-modified NK cells significantly enhanced the survival of RAG mice bearing established ip RMA-erbB2+ lymphoma. In summary, these data suggest that use of genetically modified NK cells could broaden the scope of cancer immunotherapy for patients.
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