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Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy

Nature Biotechnology volume 31, pages 928–933 (2013)Cite this article

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Abstract

Progress in adoptive T-cell therapy for cancer and infectious diseases1,2 is hampered by the lack of readily available, antigen-specific, human T lymphocytes. Pluripotent stem cells could provide an unlimited source of T lymphocytes, but the therapeutic potential of human pluripotent stem cell–derived lymphoid cells generated to date remains uncertain3,4,5,6. Here we combine induced pluripotent stem cell (iPSC)7 and chimeric antigen receptor (CAR)8 technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture. These iPSC-derived, CAR-expressing T cells display a phenotype resembling that of innate γδ T cells. Similar to CAR-transduced, peripheral blood γδ T cells, the iPSC–derived T cells potently inhibit tumor growth in a xenograft model. This approach of generating therapeutic human T cells 'in the dish' may be useful for cancer immunotherapy and other medical applications.

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Figure 1: Differentiation of 1928z CAR–engineered T-iPSCs into CD19-specific functional T lymphocytes.
Figure 2: Phenotypic profiling of 1928z-T-iPSC-T cells before and after CD19-induced expansion.
Figure 3: 1928z-T-iPSC-T cells lyse CD19-positive tumor cells in vitro and in vivo.

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Acknowledgements

We thank J. Anderson for valuable advice on γδ T-cell expansion; U.K. Bhanot and A. Manzo for their help with teratoma assay evaluation; J. Plotkin and G. Gunset for outstanding technical assistance; M. Condomines, J. Mansilla-Soto and E. Oricchio for reviewing the manuscript. This work was supported by the Sloan-Kettering Institute's Clinical Scholars Biomedical Research Training Program with funds granted by the C.A. Dana Foundation (M.T.), the Department of Defense Prostate Cancer Training Award PC101964 (C.C.K.), the Majors Family Foundation, The Lake Road Foundation, Mr. and Mrs. Mallah, and Mr. L. Sanders.

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Authors and Affiliations

  1. Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Maria Themeli, Christopher C Kloss, Victor D Fedorov, Fabiana Perna & Michel Sadelain

  2. Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Giovanni Ciriello

  3. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Mithat Gonen

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  1. Maria Themeli
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Contributions

M.T. designed the study, planned and performed experiments, analyzed and interpreted data and wrote the manuscript; C.C.K. performed experiments, helped in data analysis and edited the manuscript; G.C. analyzed and interpreted microarray data; V.D.F. helped with experiments and data analysis; F.P. helped with experiments and data analysis; M.G. chose the statistical methods and performed statistical analyses; M.S. designed the study, analyzed and interpreted data and wrote the manuscript.

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Correspondence to Michel Sadelain.

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The authors declare no competing financial interests.

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Supplementary Figures 1–9 and Supplementary Tables 1 and 2 (PDF 8778 kb)

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Themeli, M., Kloss, C., Ciriello, G. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol 31, 928–933 (2013). https://doi.org/10.1038/nbt.2678

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