An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs.
There is a growing interest in using antigen-specific T cells for the treatment of human malignancy. For example, adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) has been effective prophylaxis and treatment of EBV-associated lymphoproliferative disease in immunocompromised patients. For all immunotherapies, however, there has been a hypothetical concern that mutations in tumor-specific antigens may lead to tumor escape. We now demonstrate that such events may indeed occur, with lethal outcome. A patient who developed lymphoma after marrow transplantation received donor-derived, EBV-specific CTLs but died with progressive disease. The tumor cells proved substantially less sensitive to cytolysis than the EBV-transformed B-cell line used for CTL generation. The major cytolytic activity of the donor CTL was directed against 2 HLA-A11-restricted epitopes in the viral EBNA-3B antigen. Sequence analysis of this gene in the tumor virus revealed a 245-base pair deletion, which removed these 2 CTL epitopes. Hence, the viral antigen in the tumor had mutated in a way that allowed escape from CTLs. Analysis of EBV polymorphisms demonstrated that before CTL infusion, more than one virus was present, including a virus with wild-type EBNA-3B. After CTL infusion, only the virus with the EBNA-3B deletion could be detected, suggesting that the infused CTLs had selected a resistant strain in vivo. Such an occurrence, even when polyclonal CTL lines are used against genetically stable virus antigens, suggests that escape mutants may be a serious problem when CTL therapy is directed against more unstable tumor cell-derived targets.
Gottschalk
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S
Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Ng
C Y
CY
Perez
M
M
Smith
C A
CA
Sample
C
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Brenner
M K
MK
Heslop
H E
HE
Rooney
C M
CM
D000293:Adolescent; D000595:Amino Acid Sequence; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002461:Cell Line, Transformed / Q000276:immunology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology* / Q000635:transmission / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000276:immunology*; D017809:Fatal Outcome; D005260:Female; D005814:Genes, Viral; D015234:HLA-A Antigens / Q000276:immunology; D059870:HLA-A11 Antigen; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000009:adverse effects*; D015678:Viral Structural Proteins / Q000235:genetics*
D018906:Antineoplastic Agents, Alkylating; C422762:EBNA-3B antigen; D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D016056:Immunodominant Epitopes; D015678:Viral Structural Proteins; D003520:Cyclophosphamide