title: Functional reversion of antigen-specific CD8+ T cells from patients with Hodgkin lymphoma following in vitro stimulation with recombinant polyepitope.
abstract: Recent studies on Hodgkin's lymphoma (HL) have indicated that patients with active disease display functional impairment of Ag-specific CD8+ T cells due to expansion of regulatory T cells at sites of disease and in the peripheral blood. Adoptive cellular immunotherapy based on EBV-specific CD8+ T cells has been explored with limited success to date. It has been proposed that improved targeting of these CD8+ T cells toward viral Ags that are expressed in HL may enhance future therapeutic vaccine strategies. In this study, we have developed a novel replication-deficient adenoviral Ag presentation system that is designed to encode glycine alanine repeat-deleted EBV nuclear Ag 1 covalently linked to multiple CD8+ T cell epitopes from latent membrane proteins 1 and 2. A single stimulation of CD8+ T cells from healthy virus carriers, and patients with HL with this adenoviral construct in combination with IL-2, was sufficient to reverse the functional T cell impairment and restored both IFN-gamma production and cytolytic function. More importantly, these activated CD8+ T cells responded to tumor cells expressing membrane proteins and recognized novel EBNA1 epitopes. Flow cytometric analysis revealed that a large proportion of T cells expanded from patients with HL were CD62L(high) and CD27(high), and CCR7(low), consistent with early to mid effector T cells. These findings provide an important platform for translation of Ag-specific adoptive immunotherapy for the treatment of EBV-associated malignancies such as HL and nasopharyngeal carcinoma.
authors.affiliation: Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Road, Brisbane, Australia 4029.
authors.forename: Corey
authors.initials: C
authors.lastname: Smith
authors.forename: Leanne
authors.initials: L
authors.lastname: Cooper
authors.forename: Melinda
authors.initials: M
authors.lastname: Burgess
authors.forename: Michael
authors.initials: M
authors.lastname: Rist
authors.forename: Natasha
authors.initials: N
authors.lastname: Webb
authors.forename: Eleanore
authors.initials: E
authors.lastname: Lambley
authors.forename: Judy
authors.initials: J
authors.lastname: Tellam
authors.forename: Paula
authors.initials: P
authors.lastname: Marlton
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: Maher
authors.initials: M
authors.lastname: Gandhi
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000150:complications; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D004854:Herpesvirus 4, Human / Q000276:immunology; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000276:immunology; D014412:Tumor Virus Infections / Q000150:complications; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins