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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We would like to thank Sanofi Pasteur for funding affinity maturation of the gp100 and MAGE-A3 mTCRs; C. Yee (Fred Hutchinson Cancer Research Centre, Seattle, Washington, USA), P. Coulie (University of Louvain, Brussels, Belgium) and V. Cerundolo (Weatherall Institute of Molecular Medicine, University of Oxford, UK) for providing T cell clones; Southern Research and Cellvax for conducting mouse xenograft experiments; Southern Research for immunohistochemistry staining; R. Liu for assistance with mouse imaging and tumor measurements; K. Haines (Translational and Correlative Studies Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA) for technical support; and A. Secreto, C. Keefer and G. Danet-Desnoyers (Stem Cell and Xenograft Core, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA) for assistance with the established tumor xenograft studies.
N.L., G.B., K.J.A., T.M.M., N.J.H., J.G., F.C.B., N.J.P., N.M.L., N.E.H., P.E.M., Y.L., B.J.C., M.S., E.E.B., P.T.T., S.J.P., R.E.D., J.V.H., S.M.D., R.A., A.J., Y.M., A.V., D.D.W., D.H.S. and B.K.J. are employed by ImmunoCore Ltd., and the reagents studied in this manuscript were developed by ImmunoCore Ltd.
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