Monoclonal TCR-redirected tumor cell killing

Abstract

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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Figure 1: The biological activity and biophysical characteristics of ImmTAC molecules with different specificities.
Figure 2: Efficient activation of multiple CD8+ T cell effector functions by ImmTAC-gp100.
Figure 3: Redirected lysis of tumor cells and peptide-pulsed targets by CD8+ T cells in the presence of ImmTAC molecules.
Figure 4: Visualization of the redirected lysis of Mel642 melanoma cells by PBMCs or CD8+ T cells in the presence of ImmTAC-gp100.
Figure 5: In vivo efficacy of ImmTAC molecules in NOD-SCID and Beige-SCID xenograft models.

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Acknowledgements

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.

Author information

N.L., N.E.H., P.E.M. and E.G. isolated wild-type mTCRs and carried out the phage display process under the supervision of Y.L.; A.V. and Y.L. were involved in ImmTAC construct optimization; T.M.M., J.G., A.V., E.E.B., N.J.P., N.M.L. and B.J.C. were involved in protein production and biochemical testing; G.B., K.J.A., A.L., N.J.H., K.L., S.J.P., J.V.H. and R.E.D. performed in vitro experiments under the supervision of D.D.W., R.A., D.H.S., A.K.S. and D.A.P. Large-scale production, stability testing, quality control and biochemical testing of ImmTACs was conducted by F.C.B., M.S., A.J., E.E.B., P.T.T. and S.M.D. under the supervision of Y.M. Mouse xenograft experiments were designed, coordinated and conducted by G.P., C.H.J., M.K. and D.D.W. Data analysis and interpretation were performed by D.H.S. and D.A.P.; D.H.S. and D.A.P. wrote the paper. B.K.J. conceived the idea and directed the project. All authors contributed to discussions.

Correspondence to Bent K Jakobsen.

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Competing interests

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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