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T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells

Leukemia volume 26, pages 365–367 (2012)Cite this article

Myeloma is a plasma cell dyscrasia, which is categorized as a B-cell neoplasia. It is usually incurable with a median survival period of 3–4 years. There are serious problems in treating patients with myeloma. Myeloma cells themselves are not merely less sensitive to chemotherapy due to their dormancy but prone to becoming drug resistant. The incidence of myeloma increases with age and the median age at diagnosis is ∼70 years. Currently, several new agents, such as bortezomib, lenalidomide and thalidomide, are clinically available for single or combined use for induction and maintenance. However, results have not been satisfactory with regard to overall survival and event-free survival. Thus, new therapeutic options are needed for patients with myeloma. Myeloma cells show the strong expression of CD38, but no expression of CD19 on their surface, differing from other hematologic malignancies containing B-cell neoplasms. Generally, in normal hematopoiesis, CD38 expression on the cell surface is restricted to lineage-committed precursors.1 According to gene chip profiling, the expression of mRNA for CD38 is restricted to the thymus, bone marrow and prostate, suggesting that CD38 is a feasible target for immunotherapy. Immunotherapy including antibody treatment acts on cells, which have not entered the cell cycle and is desirable for aged patients because of fewer adverse effects. Thus, we investigated whether the retroviral vector-mediated transduction of an anti -CD38-chimeric antigen receptor (CAR) gene, which we developed previously,2 contributed to the abrogation of myeloma cells. Here we report that T-cell immunotherapy with the anti-CD38-CAR is quite effective in eliminating myeloma cells highly expressing the CD38 molecule.

Two myeloma cell lines (RPMI8226 and KMM1) were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum at 37 °C. Primary myeloma cells obtained from bone marrow aspirate of patients, peripheral blood cells from healthy donors and those from a patient (Patient 5) in autologous settings were subjected to Ficoll-density centrifugation. Informed consent was obtained from all of these patients and donors. Patients with myeloma and donors were examined as approved by the institutional review board at Hiroshima University and Fukuyama Central Hospital. The retroviral vector construct consisting of green fluorescein protein, the transmembrane domain of CD8α, the intracellular domains of 4–1BB, CD3ζ and anti-CD38 single-chain variable domain (scFv) was reported previously.2 Peripheral blood mononuclear cells stimulated with PHA-M and IL-2 were transduced in virus-conditioned medium with polybrene in a polypropylene tube coated with fibronectin by spinoculation. The addition of anti-CD38 antibody (CPK-H; MBL, Nagoya, Japan) was used to protect transduced T cells from auto-lysis through cross-linking of anti-CD38-CAR with intrinsic CD38, because activated T cells express CD38 on their cell surface.2 Briefly, to increase the number of T cells with anti-CD38-CAR and maintain the viability of the cells, we replaced the medium containing the antibody (0.15 mg/ml) and IL-2 (200 IU/ml) every 4–5 days until 14 days post-transduction. For the co-culture experiment, T cells were washed with phosphate-buffered saline and complete medium several times to eliminate the effect of residual antibodies in the medium. To detect surface expression of the anti-CD38-CAR, cells were stained with a goat anti-mouse (Fab’)2 polyclonal antibody conjugated to biotin followed by streptavidin-PerCP. Cytotoxicity of the transduced cells was assessed by flow cytometric analysis as described.2

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Acknowledgements

We thank A Ihara (Fukuyama Central Hospital) and A Sakai (Hiroshima University) for providing invaluable comments and help.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    K Mihara, J Bhattacharyya & A Kimura

  2. Department of Laboratory Medicine, Faculty of Medicine, Kagawa University, Kita-gun, Japan

    A Kitanaka

  3. Department of Life Science, Yasuda Women’s University Faculty of Pharmacy, Hiroshima, Japan

    K Yanagihara & T Kubo

  4. Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Y Takei

  5. Department of Clinical Laboratory, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan

    H Asaoku

  6. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Y Takihara

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  1. K Mihara
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Correspondence to K Mihara.

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Mihara, K., Bhattacharyya, J., Kitanaka, A. et al. T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia 26, 365–367 (2012). https://doi.org/10.1038/leu.2011.205

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