Therapeutic LMP1 polyepitope vaccine for EBV-associated Hodgkin disease and nasopharyngeal carcinoma.
Development of an epitope-based vaccination strategy designed to enhance Epstein-Barr virus (EBV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) is increasingly being considered as a preferred approach for the treatment of EBV-associated relapsed Hodgkin disease (HD) and nasopharyngeal carcinoma (NPC). EBV-encoded latent membrane proteins, LMP1 and LMP2, are the only target antigens available for therapeutic augmentation of CTL responses in patients with HD and NPC. Here, we describe preclinical studies using a recombinant poxvirus vaccine that encodes a polyepitope protein comprising 6 HLA A2-restricted epitopes derived from LMP1. Human cells infected with this recombinant polyepitope construct were efficiently recognized by LMP1-specific CTL lines from HLA A2 healthy individuals. Furthermore, immunization of HLA A2/K(b) mice with this polyepitope vaccine consistently generated strong LMP1-specific CTL responses to 5 of the 6 epitopes, which were readily detected by both ex vivo and in vitro assays. More important, this polyepitope vaccine successfully reversed the outgrowth of LMP1-expressing tumors in HLA A2/K(b) mice. These studies provide an important platform for the development of an LMP-based polyepitope vaccine as an immunotherapeutic tool for the treatment of EBV-associated HD and NPC.
Duraiswamy
Jaikumar
J
Cooperative Research Centre for Vaccine Technology, Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
Sherritt
Martina
M
Thomson
Scott
S
Tellam
Judy
J
Cooper
Leanne
L
Connolly
Geoff
G
Bharadwaj
Mandvi
M
Khanna
Rajiv
R
D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002277:Carcinoma / Q000276:immunology / Q000628:therapy* / Q000821:virology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006183:H-2 Antigens / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009303:Nasopharyngeal Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology; D019444:Vaccines, DNA / Q000627:therapeutic use*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000956:Antigens, Viral; D019496:Cancer Vaccines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015789:HLA-A2 Antigen; D019444:Vaccines, DNA; D014763:Viral Matrix Proteins; D007371:Interferon-gamma