Monoclonal TCR-redirected tumor cell killing
T cell receptor (TCR)-based immunotherapeutic approaches have so far had limited success because of a lack of specific immune recognition and activation by the TCR. Here Nathaniel Liddy and his colleagues describe the generation, optimization and characterization of a new set of reagents—immune-mobi...
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Veröffentlicht in: | Nature medicine 2012-06, Vol.18 (6), p.980-987 |
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Sprache: | eng |
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Zusammenfassung: | T cell receptor (TCR)-based immunotherapeutic approaches have so far had limited success because of a lack of specific immune recognition and activation by the TCR. Here Nathaniel Liddy and his colleagues describe the generation, optimization and characterization of a new set of reagents—immune-mobilizing monoclonal TCRs against cancer (or ImmTACs)—designed to overcome some of these limitations. The ImmTACs were used to redirect and activate T cells to lyse tumor cells both
in vitro
and
in vivo
, even those expressing very low epitope numbers on the cell surface.
T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth
in vivo
. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy. |
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ISSN: | 1078-8956 1546-170X |
DOI: | 10.1038/nm.2764 |