Functional reversion of antigen-specific CD8+ T cells from patients with Hodgkin lymphoma following in vitro stimulation with recombinant polyepitope.
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.
Smith
Corey
C
Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Road, Brisbane, Australia 4029.
Cooper
Leanne
L
Burgess
Melinda
M
Rist
Michael
M
Webb
Natasha
N
Lambley
Eleanore
E
Tellam
Judy
J
Marlton
Paula
P
Seymour
John F
JF
Gandhi
Maher
M
Khanna
Rajiv
R
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*
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