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Effective Treatment of Refractory CMV Reactivation After Allogeneic Stem Cell Transplantation With In Vitro-generated CMV pp65-specific CD8+ T-cell Lines

Meij, Pauline*; Jedema, Inge; Zandvliet, Maarten L.*; van der Heiden, Pim L. J.; van de Meent, Marian; van Egmond, H. M. Esther; van Liempt, Ellis; Hoogstraten, Conny; Kruithof, Simone; Veld, Sabrina; Marijt, Erik W. A.; von dem Borne, Peter A.; Lankester, Arjan C.; Halkes, Constantijn J. M.; Falkenburg, J. H. Frederik

doi: 10.1097/CJI.0b013e31826e35f6
Clinical Studies

To treat patients with refractory cytomegalovirus (CMV) reactivation after allogeneic stem cell transplantation, a phase I/II clinical study on adoptive transfer of in vitro-generated donor-derived or patient-derived CMV pp65-specific CD8+ T-cell lines was performed. Peripheral blood mononuclear cells from CMV seropositive donors or patients were stimulated with HLA-A*0201-restricted and/or HLA-B*0702-restricted CMV pp65 peptides (NLV/TPR) and 1 day after stimulation interferon-γ)-producing cells were enriched using the CliniMACS Cytokine Capture System (interferon-γ), and cultured with autologous feeders and low-dose interluekin-2. After 7–14 days of culture, quality controls were performed and the CMV-specific T-cell lines were administered or cryopreserved. The T-cell lines generated contained 0.6–17×106 cells, comprising 54%–96% CMV pp65-specific CD8+ T cells, and showed CMV-specific lysis of target cells. Fifteen CMV-specific T-cell lines were generated of which 8 were administered to patients with refractory CMV reactivation. After administration, no acute adverse events and no graft versus host disease were observed and CMV load disappeared. In several patients, a direct relation between administration of the T-cell line and the in vivo appearance of CMV pp65-specific T cells could be documented. In conclusion, administration of CMV pp65-specific CD8+ T-cell lines was found to be feasible and safe, and enduring efficacy of administered CMV pp65-specific CD8+ T-cell lines could be demonstrated.

Departments of *Clinical Pharmacy and Toxicology

Hematology

Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

Reprints: Pauline Meij, Department of Clinical Pharmacy and Toxicology, L0-P, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (e-mail: p.meij@lumc.nl).

Received November 18, 2011

Accepted August 8, 2012

© 2012 Lippincott Williams & Wilkins, Inc.