Effective treatment of refractory CMV reactivation after allogeneic stem cell transplantation with in vitro-generated CMV pp65-specific CD8+ T-cell lines

J Immunother. 2012 Oct;35(8):621-8. doi: 10.1097/CJI.0b013e31826e35f6.

Abstract

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 × 10(6) 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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Line
  • Cytotoxicity, Immunologic
  • HLA-A2 Antigen / metabolism
  • HLA-B7 Antigen / metabolism
  • Herpes Simplex / etiology
  • Herpes Simplex / immunology
  • Herpes Simplex / therapy*
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Phosphoproteins / immunology
  • Phosphoproteins / metabolism
  • Postoperative Complications*
  • Protein Binding
  • Simplexvirus / physiology*
  • Stem Cell Transplantation*
  • Transplantation, Homologous
  • Viral Load / immunology
  • Viral Matrix Proteins / immunology
  • Viral Matrix Proteins / metabolism
  • Virus Activation

Substances

  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • HLA-B*07:02 antigen
  • HLA-B7 Antigen
  • Interleukin-2
  • Peptide Fragments
  • Phosphoproteins
  • Viral Matrix Proteins
  • cytomegalovirus matrix protein 65kDa
  • Interferon-gamma