4.5 Article

Epstein-Barr virus-specific cytokine-induced killer cells for treatment of Epstein-Barr virus-related malignant lymphoma

Journal

CYTOTHERAPY
Volume 20, Issue 6, Pages 839-850

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.jcyt.2018.04.005

Keywords

cytokine-induced killer cells; cytotoxic T cells; Epstein-Barr virus; immunotherapy; lymphoma; post-transplantation lymphoproliferative disease

Funding

  1. Hessen State Ministry of Higher Education, Research and the Arts [III L 4-518/17.004]
  2. Else Kroner-Fresenius-Stiftung [P75/08//A62/08, 2014_A305]

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Background. Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific antitumor and virus-specific cellular immunity may be applied in this context. Methods. CIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-gamma, anti-CD3, interleukin (IL)-2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities. Results. Pre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. In vitro cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity. Discussion. The transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD.

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