An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs

Blood - Tập 97 Số 4 - Trang 835-843 - 2001
Stephen Gottschalk1,2, Catherine Y. Ng1,2, Monika W. Perez1,2, Colton A. Smith1,2, Clare E. Sample1,2, Malcolm K. Brenner1,2, Helen E. Heslop1,2, Cliona M. Rooney1,2
1From the Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX; and St Jude Children's Research Hospital, Memphis, TN.
2St Jude Children’s Research Hospital, Memphis, TN

Tóm tắt

AbstractThere 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.

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Blood

Tập 97 Số 4

835-843

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