Monoclonal TCR-redirected tumor cell killing.
Liddy N., Bossi G., Adams KJ., Lissina A., Mahon TM., Hassan NJ., Gavarret J., Bianchi FC., Pumphrey NJ., Ladell K., Gostick E., Sewell AK., Lissin NM., Harwood NE., Molloy PE., Li Y., Cameron BJ., Sami M., Baston EE., Todorov PT., Paston SJ., Dennis RE., Harper JV., Dunn SM., Ashfield R., Johnson A., McGrath Y., Plesa G., June CH., Kalos M., Price DA., Vuidepot A., Williams DD., Sutton DH., Jakobsen BK.
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.