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Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma

Gene Therapy volume 20, pages 386–395 (2013)Cite this article

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Abstract

The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157–165 in the context of HLA-A*02:01 to re-direct autologous CD8+ T cells towards NY-ESO-1+ myeloma cells. These re-directed T cells specifically lysed NY-ESO-1157–165/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7− re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7+ memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1157–165/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.

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Acknowledgements

We would like to thank S Kleber, M Storz and M Glönkler for excellent technical assistance. Furthermore, we thank S Böttcher and R Müller (Department of Hematology, University Hospital Zurich, Switzerland) for support with flow cytometry. We thank P Romero (LICR, Lausanne, Switzerland) for the HLA-A*02:01-restricted NY-ESO-1157–165 (SLLMWITQC) peptide-specific, PE-conjugated tetramer. This study was funded by the ‘Dr Arnold U. und Susanne Huggenberger-Bischoff Stiftung zur Krebsforschung’ (UP); Cancer Research Institute; Ludwig Institute of Cancer Research; Krebsliga Zurich (all CR).

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Author notes

  1. P C Schuberth, G Jakka, C Renner and U Petrausch: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, University Hospital Zurich, Zürich, Switzerland

    P C Schuberth, G Jakka, A Wadle, F Gautschi, A Mischo, M Thiel, C Renner & U Petrausch

  2. Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Providence Cancer Center and Providence Portland Medical Center, Portland, OR, USA

    S M Jensen & B A Fox

  3. Immunological Monitoring Laboratory, Earle A. Chiles Research Institute, Providence Cancer Center and Providence Portland Medical Center, Portland, OR, USA

    D Haley

  4. Biostatistics Unit, Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland

    S Haile

  5. Department of Internal Medicine I, Saarland University Medical School, Homburg, Germany

    G Held

  6. Institute of Surgical Pathology, University Hospital Zurich, Zürich, Switzerland

    M Tinguely

  7. Department of Pathology, Providence Portland Medical Center, Portland, OR, USA

    C B Bifulco

  8. Department of Immunology, University Hospital Zurich, Zürich, Switzerland

    C Renner & U Petrausch

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  1. P C Schuberth
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Correspondence to U Petrausch.

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Schuberth, P., Jakka, G., Jensen, S. et al. Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma. Gene Ther 20, 386–395 (2013). https://doi.org/10.1038/gt.2012.48

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