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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References

  1. 1.

    et al. Graft-versus-myeloma effect: proof of principle. Blood 87, 1196–1198 (1996).

  2. 2.

    et al. T cell–depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 98, 934–939 (2001).

  3. 3.

    et al. The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood 103, 4362–4364 (2004).

  4. 4.

    et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 89, 789–793 (1997).

  5. 5.

    et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N. Engl. J. Med. 335, 91–97 (1996).

  6. 6.

    et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N. Engl. J. Med. 348, 1875–1883 (2003).

  7. 7.

    et al. Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma. Blood 98, 579–585 (2001).

  8. 8.

    & Timely reconstitution of immune competence affects clinical outcome following autologous stem cell transplantation. Clin. Exp. Med. 4, 78–85 (2004).

  9. 9.

    , & T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells. Proc. Natl. Acad. Sci. USA 99, 13009–13013 (2002).

  10. 10.

    et al. Activated marrow-infiltrating lymphocytes effectively target plasma cells and their clonogenic precursors. Cancer Res. 65, 2026–2034 (2005).

  11. 11.

    et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat. Med. 11, 1230–1237 (2005).

  12. 12.

    et al. Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood 117, 788–797 (2011).

  13. 13.

    et al. Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. Clin. Cancer Res. 20, 1355–1365 (2014).

  14. 14.

    et al. Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of costimulated autologous T cells. Clin. Cancer Res. 15, 4499–4507 (2009).

  15. 15.

    et al. Transfer of influenza vaccine-primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trial. Blood 117, 63–71 (2011).

  16. 16.

    et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin. Cancer Res. 19, 3640–3648 (2013).

  17. 17.

    , & Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

  18. 18.

    et al. Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies. Eur. J. Immunol. 42, 3174–3179 (2012).

  19. 19.

    et al. Quantifying and imaging NY-ESO-1/LAGE-1-derived epitopes on tumor cells using high affinity T cell receptors. J. Immunol. 176, 7308–7316 (2006).

  20. 20.

    , , & New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape. Curr. Opin. Immunol. 27, 16–25 (2014).

  21. 21.

    et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

  22. 22.

    et al. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int. J. Hematol. 99, 361–371 (2014).

  23. 23.

    et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, p517–p528 (2014).

  24. 24.

    et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

  25. 25.

    et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114, 535–546 (2009).

  26. 26.

    , , & Lack of specific gamma-retroviral vector long terminal repeat promoter silencing in patients receiving genetically engineered lymphocytes and activation upon lymphocyte restimulation. Blood 114, 2888–2899 (2009).

  27. 27.

    et al. Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat. Biotechnol. 23, 349–354 (2005).

  28. 28.

    et al. Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J. Immunol. 180, 6116–6131 (2008).

  29. 29.

    et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).

  30. 30.

    et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: Long term follow up and correlates with response. Clin. Cancer Res. (2014).

  31. 31.

    et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).

  32. 32.

    et al. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc. Natl. Acad. Sci. USA 105, 20410–20415 (2008).

  33. 33.

    et al. Genes encoding tumor-specific antigens are expressed in human myeloma cells. Blood 94, 1156–1164 (1999).

  34. 34.

    et al. The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation. Blood 106, 167–174 (2005).

  35. 35.

    et al. Cancer/testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis. J. Immunol. 178, 3307–3315 (2007).

  36. 36.

    et al. Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation. Blood 109, 1103–1112 (2007).

  37. 37.

    et al. NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses. Blood 105, 3939–3944 (2005).

  38. 38.

    et al. Improved endpoints for cancer immunotherapy trials. J. Natl. Cancer Inst. 102, 1388–1397 (2010).

  39. 39.

    et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

  40. 40.

    , & Toxicity management for patients receiving novel T-cell engaging therapies. Curr. Opin. Pediatr. 26, 43–49 (2014).

  41. 41.

    et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828 (2011).

  42. 42.

    et al. T-cell immunotherapy: looking forward. Mol. Ther. 22, 1564–1574 (2014).

  43. 43.

    et al. Genetically engineered NY-ESO-1 specific T cells in HLA-A201+ patients with advanced cancers. J. Clin. Oncol. 33, TPS3102 (2015).

  44. 44.

    et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci. Transl. Med. 5, 197ra103 (2013).

  45. 45.

    et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122, 863–871 (2013).

  46. 46.

    & Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39, 49–60 (2013).

  47. 47.

    et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat. Med. 16, 198–204 (2010).

  48. 48.

    et al. Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. J. Immunol. 159, 5921–5930 (1997).

  49. 49.

    et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4, 132ra153 (2012).

  50. 50.

    et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 12, 1195–1203 (2011).

  51. 51.

    et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J. Clin. Oncol. 31, 3279–3287 (2013).

  52. 52.

    Novel strategies in the treatment of relapsed/refractory multiple myeloma. From the Multiple Myeloma Research Foundation. Oncology 17, 1063–1065 (2003).

  53. 53.

    et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J. Clin. Oncol. 31, 4199–4206 (2013).

  54. 54.

    et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer immunology immunotherapy 58, 1033–1045 (2009).

  55. 55.

    et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J. Clin. Invest. 118, 2427–2437 (2008).

  56. 56.

    & Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

  57. 57.

    et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117, 4691–4695 (2011).

  58. 58.

    et al. Atypical serum immunofixation patterns frequently emerge in immunomodulatory therapy and are associated with a high degree of response in multiple myeloma. Br. J. Haematol. 143, 654–660 (2008).

  59. 59.

    et al. A third-generation lentivirus vector with a conditional packaging system. J. Virol. 72, 8463–8471 (1998).

  60. 60.

    et al. “MIATA”-minimal information about T cell assays. Immunity 31, 527–528 (2009).

  61. 61.

    et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

  62. 62.

    et al. Comprehensive assessment of T cell receptor beta-chain diversity in alphabeta T cells. Blood 114, 4099–4107 (2009).

  63. 63.

    Joint Models for Longitudinal and Time-to-Event Data (Chapman & Hall/CRC, 2012).

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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.

Author information

Author notes

    • Aaron P Rapoport
    • , Edward A Stadtmauer
    • , Gwendolyn K Binder-Scholl
    •  & Michael Kalos

    These authors contributed equally to this work.

Affiliations

  1. The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Aaron P Rapoport
    • , Olga Goloubeva
    • , Ashraf Z Badros
    • , Shari Kronsberg
    • , Saul Yanovich
    • , Nancy Hardy
    • , Jean Yared
    • , Sunita Philip
    •  & Sandra Westphal
  2. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Edward A Stadtmauer
    • , Dan T Vogl
    • , Simon F Lacey
    • , Alfred Garfall
    • , Brendan Weiss
    • , Irina Kulikovskaya
    • , Minnal Gupta
    • , Don L Siegel
    • , Bruce L Levine
    • , Michael Kalos
    •  & Carl H June
  3. Adaptimmune Ltd, Oxford, UK.

    • Gwendolyn K Binder-Scholl
    • , Luca Melchiori
    • , Joanna E Brewer
    • , Alan D Bennett
    • , Andrew B Gerry
    • , Nicholas J Pumphrey
    • , Daniel Williams
    • , Helen K Tayton- Martin
    • , Lilliam Ribeiro
    • , Tom Holdich
    •  & Bent K Jakobsen
  4. Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Olga Goloubeva
    • , Jeffrey Finklestein
    •  & Shari Kronsberg
  5. Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Simon F Lacey
    • , Jeffrey Finklestein
    • , Irina Kulikovskaya
    • , Minnal Gupta
    • , Naseem Kerr
    • , Don L Siegel
    • , Bruce L Levine
    • , Michael Kalos
    •  & Carl H June
  6. School of Mathematics and Statistics, Carleton University, Ottawa, Ontario, Canada.

    • Sanjoy K Sinha
  7. Cambridge Biomedical, Cambridge, Massachusetts, USA.

    • Sarah Bond

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Contributions

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.

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.

Corresponding author

Correspondence to Carl H June.

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https://doi.org/10.1038/nm.3910

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