title: Early immune response against retrovirally transduced herpes simplex virus thymidine kinase-expressing gene-modified T cells coinfused with a T cell-depleted marrow graft: an altered immune response?
abstract: Administration of herpes simplex thymidine kinase (HSV-tk)-expressing, gene-modified T cells (GMCs) with T cell-depleted bone marrow transplantation (TCD-BMT) can allow modulation of posttransplantation alloreactivity. Twelve patients received 2 x 10(5) to 2 x 10(6) CD3+ donor GMCs per kilogram with HLA-identical sibling TCD-BMT. Despite extensive T cell depletion of bone marrow, an intensive conditioning regimen, and immunosuppressive graft-versus-host disease (GvHD) prophylaxis, infusion at the time of TCD-BMT of this low number of GMCs sufficed to induce a rapid GMC-specific immune response, as detected by interferon- enzyme- linked immunospot assay in six of eight patients, preferentially targeting HSV-tk. Maximal responses were reached early (median time, 49 [35-68] days post-BMT), with a subsequent rapid and significant decrease in five of six evaluable patients. Immune responses were negatively correlated with the maximal circulating GMC counts. However, such immune response did not result in the elimination of circulating GMCs and was not associated with measurable ex vivo cytotoxic activity against GMCs. Furthermore, alloreactive GMCs still could induce GCV-sensitive GvHD in one patient despite an ongoing immune response. Overall, infusion of HSV-tk-expressing GMCs at the time of BMT results in an early immune response. Such immune response may be altered and may not prevent persistent GCV-sensitive alloreactivity.
authors.affiliation: INSERM, U645, 25020 Besançon, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Mercier-Letondal
authors.forename: Marina
authors.initials: M
authors.lastname: Deschamps
authors.forename: Delphine
authors.initials: D
authors.lastname: Sauce
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Certoux
authors.forename: Noël
authors.initials: N
authors.lastname: Milpied
authors.forename: Bruno
authors.initials: B
authors.lastname: Lioure
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Cahn
authors.forename: Eric
authors.initials: E
authors.lastname: Deconinck
authors.forename: Christophe
authors.initials: C
authors.lastname: Ferrand
authors.forename: Pierre
authors.initials: P
authors.lastname: Tiberghien
authors.forename: Eric
authors.initials: E
authors.lastname: Robinet
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005822:Genetic Vectors; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008875:Middle Aged; D009355:Neomycin / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D013937:Thymidine Kinase / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000235:genetics
chemical_list: D014764:Viral Proteins; D013937:Thymidine Kinase; D009355:Neomycin