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Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells

Gene Therapy volume 18, pages 509–516 (2011)Cite this article

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Abstract

Multiple myeloma causes approximately 10% of all hematologic malignancies. We have previously shown that human T cells expressing chimeric NKG2D receptors (chNKG2D) consisting of NKG2D fused to the CD3ζ cytoplasmic domain secrete proinflammatory cytokines and kill human myeloma cells. In this study, we show chNKG2D T cells are effective in a murine model of multiple myeloma. Mice with established 5T33MM–green fluorescent protein tumors were treated with one or two infusions of chNKG2D T cells. Compared with mice treated with T cells expressing wild type (wt)NKG2D receptors, a single dose of chNKG2D T cells increased survival, with half of the chNKG2D T-cell-treated mice surviving long term. Two infusions of chNKG2D T cells led to tumor-free survival in all mice. ChNKG2D T cells were located at sites of tumor growth, including the bone marrow and spleen after intravenous injection. There was an increase in activated host T cells and NK cells at tumor sites and in serum interferon-γ after chNKG2D T-cell injection. Surviving mice were able to resist a rechallenge with 5T33MM cells but not RMA lymphoma cells, indicating that the mice developed a protective, specific memory response. These data demonstrate that chNKG2D T cells may be an effective adoptive cellular therapy for multiple myeloma.

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Acknowledgements

We thank Karin Vanderkerken for the 5T33MM tumor cells, Gary Ward and Alice Givan at the Englert Cell Analysis Laboratory for assistance with flow cytometry (Norris Cotton Cancer Center, Lebanon, NH, USA), and the Animal Resource Center at Dartmouth Medical School for help with the animal studies. We also thank Randy Noelle for helpful comments on the study design and paper. This work was supported in part by grants from the Norris Cotton Cancer Center at Dartmouth Medical School, Department of Microbiology and Immunology, and National Institutes of Health (CA130911, T32 AI07363, P20 RR16437 (KRM)). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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  1. Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH, USA

    A Barber & C L Sentman

  2. Section of Hematology/Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    K R Meehan

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Correspondence to C L Sentman.

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The technology described in this paper is licensed by Celdara Medical, LLC. Dr Sentman and Celdara are developing the technology for clinical use. If they are successful, Dr Sentman will receive compensation. This arrangement is under compliance with the policies of Dartmouth College.

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Barber, A., Meehan, K. & Sentman, C. Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther 18, 509–516 (2011). https://doi.org/10.1038/gt.2010.174

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