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Immunotherapy

Fully human CD19-specific chimeric antigen receptors for T-cell therapy

Leukemia volume 31, pages 2191–2199 (2017)Cite this article

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Abstract

Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA libraries. CARs were constructed in various formats from several scFvs and used to transduce primary human T-cells. The resulting CD19-CAR T-cells were specifically activated by CD19-positive tumor cell lines and primary chronic lymphocytic leukemia cells, and eliminated human lymphoma xenografts in immunodeficient mice. Certain fully human CAR constructs were superior to the FMC63-CAR, which is widely used in clinical trials. Imaging of cell surface distribution of the human CARs revealed no evidence of clustering without target cell engagement, and tonic signaling was not observed. To further reduce potential immunogenicity of the CARs, we also modified the fusion sites between different CAR components. The described fully human CARs for a validated clinical target may reduce immune rejection compared with murine-based CARs.

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Acknowledgements

We thank Melissa Comstock and Don Parilla (Shared Resources, Fred Hutchinson Cancer Research Center) for expertise in performing mouse experiments. This work was supported by grants from the National Institutes of Health CA136551 and CA114536 (to SRR) and Juno Therapeutics, Inc.

Author contributions

DS designed and performed research, analyzed data, and wrote the manuscript; TH, SMS and AIS designed and performed research and analyzed data; YC and KMM provided expert advice and analyzed data; and SRR designed research, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA

    D Sommermeyer, T Hill, A I Salter & S R Riddell

  2. Juno Therapeutics, Inc., Seattle, WA, USA

    S M Shamah, Y Chen & K M Mohler

  3. Department of Medicine, University of Washington, Seattle, WA, USA

    S R Riddell

  4. Technical University of Munich, Institute for Advanced Study, Munich, Germany

    S R Riddell

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  1. D Sommermeyer
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Correspondence to S R Riddell.

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SRR is founder and shareholder of Juno Therapeutics, Inc.

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Sommermeyer, D., Hill, T., Shamah, S. et al. Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia 31, 2191–2199 (2017). https://doi.org/10.1038/leu.2017.57

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