Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease.
Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease.
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DOI：
10.1182/blood-2006-11-059139
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发表时间：
2007-10
期刊：
影响因子：
20.3
通讯作者：
B. Savoldo;C. Rooney;A. Di Stasi;H. Abken;A. Hombach;A. Foster;L. Zhang;H. Heslop;M. Brenner;G. Dotti
中科院分区：
文献类型：
--
作者：
B. Savoldo;C. Rooney;A. Di Stasi;H. Abken;A. Hombach;A. Foster;L. Zhang;H. Heslop;M. Brenner;G. Dotti
过继转移EB病毒(EBV)特异性细胞毒性T淋巴细胞(EBV-CTL)表明，这些细胞在EBV(+)霍奇金淋巴瘤(HD)患者体内持续存在，产生完全的肿瘤反应。然而，如果肿瘤中的一群恶性细胞缺乏或失去EBV抗原的表达，就会发生治疗失败。因此，我们决定是否可以制备EBV-CTL，在保持其天然受体赋予的抗肿瘤活性的同时，表达针对CD30的嵌合抗原受体(CAR)，CD30是一种在恶性Hodgkin Reed-Sternberg细胞上高度且一致表达的分子。我们制作了CD30CAR，在健康供者和HD患者产生的EBV-CTL中分别有26%(+/-11%)和22%(+/-5%)表达CD30CAR。CD30CAR(+)CTL通过其天然受体杀伤自体EBV(+)细胞，并通过其主要组织相容性复合体(MHC)非限制性CAR杀伤EBV(-)/CD30(+)靶细胞。活化的T细胞亚群也表达CD30，但CD30CAR(+)CTL不损害细胞免疫反应，可能是因为正常T细胞表达较低水平的靶抗原。在异种移植模型中，CD30CAR(+)EBV-CTL可以被EBV感染的细胞共刺激，甚至对EBV(-)/CD30(+)肿瘤产生抗肿瘤作用。因此，同时表达天然抗原受体和嵌合抗原受体的EBV-CTL可能对HD的治疗具有附加价值。
Adoptive transfer of Epstein Barr virus (EBV)-specific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV(+) Hodgkin lymphoma (HD) to produce complete tumor responses. Treatment failure, however, occurs if a subpopulation of malignant cells in the tumor lacks or loses expression of EBV antigens. We have therefore determined whether we could prepare EBV-CTLs that retained the antitumor activity conferred by their native receptor while expressing a chimeric antigen receptor (CAR) specific for CD30, a molecule highly and consistently expressed on malignant Hodgkin Reed-Sternberg cells. We made a CD30CAR and were able to express it on 26% (+/- 11%) and 22% (+/- 5%) of EBV-CTLs generated from healthy donors and HD patients, respectively. These CD30CAR(+) CTLs killed both autologous EBV(+) cells through their native receptor and EBV(-)/CD30(+) targets through their major histocompatibility complex (MHC)-unrestricted CAR. A subpopulation of activated T cells also express CD30, but the CD30CAR(+) CTLs did not impair cellular immune responses, probably because normal T cells express lower levels of the target antigen. In a xenograft model, CD30CAR(+) EBV-CTLs could be costimulated by EBV-infected cells and produce antitumor effects even against EBV(-)/CD30(+) tumors. EBV-CTLs expressing both a native and a chimeric antigen receptor may therefore have added value for treatment of HD.