An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs
An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs
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DOI：
10.1182/blood.v97.4.835
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发表时间：
2001-02-15
期刊：
影响因子：
20.3
通讯作者：
Rooney, CM
中科院分区：
文献类型：
--
作者：
Gottschalk, S;Ng, CYC;Rooney, CM
人们对使用抗原特异性T细胞治疗人类恶性肿瘤越来越感兴趣。例如，eb病毒（EBV）特异性细胞毒性T淋巴细胞（ctl）的过继转移已成为免疫功能低下患者eb病毒相关淋巴细胞增生性疾病的有效预防和治疗方法。然而，对于所有的免疫疗法，一直存在一种假设的担忧，即肿瘤特异性抗原的突变可能导致肿瘤逃逸。我们现在证明，这样的事件确实可能发生，并造成致命的后果。一名骨髓移植后发生淋巴瘤的患者接受了供体来源的ebv特异性ctl，但因疾病进展而死亡。肿瘤细胞对细胞溶解的敏感性明显低于ebv转化的用于CTL生成的b细胞系。供体CTL的主要细胞溶解活性是针对病毒EBNA-3B抗原中的2个hla - a11限制性表位。该基因在肿瘤病毒中的序列分析显示245个碱基对缺失，这两个CTL表位被移除。因此，肿瘤中的病毒抗原发生了突变，允许从CTL中逃逸。EBV多态性分析表明，在CTL输注之前，存在不止一种病毒，包括一种野生型EBNA-3B病毒。CTL输注后，只检测到EBNA-3B缺失的病毒，提示输注的CTL在体内选择了耐药毒株。即使多克隆CTL系用于对抗遗传稳定的病毒抗原，这种情况也表明，当CTL治疗针对更不稳定的肿瘤细胞源性靶标时，逃逸突变可能是一个严重的问题。(C) 2001年由美国血液学会出版。
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) las 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 wildtype 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. (C) 2001 by The American Society of Hematology.