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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Nature medicine 2012-06, Vol.18 (6), p.980-987
Hauptverfasser: Liddy, Nathaniel, Bossi, Giovanna, Adams, Katherine J, Lissina, Anna, Mahon, Tara M, Hassan, Namir J, Gavarret, Jessie, Bianchi, Frayne C, Pumphrey, Nicholas J, Ladell, Kristin, Gostick, Emma, Sewell, Andrew K, Lissin, Nikolai M, Harwood, Naomi E, Molloy, Peter E, Li, Yi, Cameron, Brian J, Sami, Malkit, Baston, Emma E, Todorov, Penio T, Paston, Samantha J, Dennis, Rebecca E, Harper, Jane V, Dunn, Steve M, Ashfield, Rebecca, Johnson, Andy, McGrath, Yvonne, Plesa, Gabriela, June, Carl H, Kalos, Michael, Price, David A, Vuidepot, Annelise, Williams, Daniel D, Sutton, Deborah H, Jakobsen, Bent K
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
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.
ISSN:1078-8956
1546-170X
DOI:10.1038/nm.2764