The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs
Abstract
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.
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Cites
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Cited by
Bollard, C. M., Gottschalk, S., Torrano, V., Diouf, O., Ku, S., Hazrat, Y., Carrum, G., Ramos, C., Fayad, L., Shpall, E. J., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.51.5304 · Cited by 503
Self-citationPost-Transplant Lymphoproliferative Disorders
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Self-citationCellular therapy for multiple pathogen infections after hematopoietic stem cell transplant
Sutrave, G., Blyth, E., & Gottlieb, D. J. (2017) · Cytotherapy · doi:10.1016/j.jcyt.2017.07.012 · Cited by 20
Metadata
- Authors
- Gottschalk, S., Ng, C. Y. C., Perez, M., Smith, C. A., Sample, C., Brenner, M. K., Heslop, H. E., & Rooney, C. M.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2001-02-15
- Volume
- 97
- Issue
- 4
- Pages
- 835-843
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2036495551
- Cited by
- 271
- References
- 33
- FWCI
- 9.77
- Type
- journal article
- Language
- en
- Open access
- closed
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- Gottschalk, S., Ng, C. Y. C., Perez, M., Smith, C. A., Sample, C., Brenner, M. K., Heslop, H. E., & Rooney, C. M. (2001). An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. Blood. https://doi.org/10.1182/blood.v97.4.835
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