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NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma

Abstract

Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 109 engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1–LAGE-1 TCR–engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.

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Figure 1: Overview of clinical study.
Figure 2: Persistence and function of gene-modified cells in blood and marrow.
Figure 3: Tumor and T cell infiltration in marrow.
Figure 4: Clinical response in patient 250 correlates with engineered T cell expansion.
Figure 5: CD138, LAGE-1 and NY-ESO-1 expression in marrow.
Figure 6: Clinical responses and durability.

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Acknowledgements

We thank the staff of the Clinical Cell and Vaccine Production Facility and the Translational and Correlative Sciences Laboratory at the University of Pennsylvania, apheresis centers and nurses of the BMT programs of the University of Maryland Greenebaum Cancer Center and the Abramson Cancer Center for outstanding clinical care provide to our patients. We also thank the courageous and visionary patients who agreed to participate in this study. This work was supported in part by a grant from the US National Institutes of Health to A.P.R. and M.K. (R01-CA166961), a Senior Investigator Award to A.P.R. from the Multiple Myeloma Research Foundation (MMRF) and a sponsored research grant from Adaptimmune to M.K. and C.H.J.

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A.P.R., E.A.S., C.H.J., M.K. and G.K.B.-S. designed and carried out the study and wrote the manuscript. O.G. and S.K.S. performed statistical analysis. D.T.V., A.Z.B., S.Y., N.H., J.Y., A.G. and B.W. treated patients on study. T.H. provided clinical safety oversight. S.F.L., J.F., I.K., S.K.S., S.K., M.G., S.B., L.M. and D.W. performed correlative studies. J.E.B., A.D.B., A.B.G., N.J.P., H.K.T.-M. and B.K.J. developed the NY-ESO TCR. N.K., L.R., S.W. and S.P. were clinical coordinators for the study. D.L.S. and B.L.L. performed cell manufacturing.

Corresponding author

Correspondence to Carl H June.

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Competing interests

This study was funded in part by Adaptimmune Ltd., and the following authors are employed by Adaptimmune: G.K.B.-S., L.M., J.E.B., A.D.B., A.B.G., N.J.P., D.W., H.K.T.-M., L.R. and T.H.

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Rapoport, A., Stadtmauer, E., Binder-Scholl, G. et al. NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 21, 914–921 (2015). https://doi.org/10.1038/nm.3910

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