Immunotherapeutic strategies to prevent and treat human herpesvirus 6 reactivation after allogeneic stem cell transplantation

• Published in: Blood Vol. 121; no. 1; pp. 207 - 218
• Main Authors: Gerdemann, Ulrike, Keukens, Laura, Keirnan, Jacqueline M., Katari, Usha L., Nguyen, Chinh T.Q., de Pagter, Anne P., Ramos, Carlos A., Kennedy-Nasser, Alana, Gottschalk, Stephen M., Heslop, Helen E., Brenner, Malcolm K., Rooney, Cliona M., Leen, Ann M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 03.01.2013; Americain Society of Hematology; American Society of Hematology
• Subjects: Antigens, Viral - immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured - immunology; Coculture Techniques; Cytomegalovirus - immunology; Cytotoxicity, Immunologic; Forkhead Transcription Factors - analysis; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation - adverse effects; Herpesvirus 6, Human - immunology; Herpesvirus 6, Human - isolation & purification; Herpesvirus 6, Human - physiology; Human herpesvirus 6; Humans; Immunobiology; Immunocompromised Host; Immunodominant Epitopes - immunology; Immunotherapy, Adoptive; Lymphocyte Activation; Medical sciences; Monocytes - immunology; Roseolovirus Infections - prevention & control; Roseolovirus Infections - therapy; T-Cell Antigen Receptor Specificity; Transplantation; Transplantation, Homologous - adverse effects; Virus Activation - immunology; Prevention; Reactivation; Treatment; Allogeneic hematopoietic stem cell transplantation; Hematology; Stem cell; Hematopoietic cell; Homograft; Graft; Human herpesvirus 6
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-05-430413

Human herpesvirus (HHV) 6 causes substantial morbidity and mortality in the immunocompromised host and has no approved therapy. Adoptive transfer of virus specific T cells has proven safe and apparently effective as prophylaxis and treatment of other virus infections in immunocompromised patients; however, extension to subjects with HHV6 has been hindered by the paucity of information on targets of cellular immunity. We now characterize the cellular immune response from 20 donors against 5 major HHV6B antigens predicted to be immunogenic and define a hierarchy of immunodominance of antigens based on the frequency of responding donors and the magnitude of the T-cell response. We identified specific epitopes within these antigens and expanded the HHV6 reactive T cells using a GMP-compliant protocol. The expanded population comprised both CD4+ and CD8+ T cells that were able to produce multiple effector cytokines and kill both peptide-loaded and HHV6B wild-type virus-infected target cells. Thus, we conclude that adoptive T-cell immunotherapy for HHV6 is a practical objective and that the peptide and epitope tools we describe will allow such cells to be prepared, administered, and monitored in human subjects. •We have characterized, for the first time, the cellular immune response to HHV6 and defined a hierarchy of immunodominance.•We have developed a GMP-compliant approach to generate polyfunctional T-cell lines that effectively kill HHV6-infected cells and are suitable for clinical use.