接受针对 Epstein-Barr 病毒潜伏膜蛋白的自体细胞毒性 T 淋巴细胞治疗的淋巴瘤患者获得持续完全缓解。
Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.
机构信息
Catherine M. Bollard, Stephen Gottschalk, Vicky Torrano, Oumar Diouf, Stephanie Ku, Yasmin Hazrat, George Carrum, Carlos Ramos, Hao Liu, Meng-Fen Wu, Andrea M. Sheehan, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine and Texas Children's Hospital; Catherine M. Bollard, Stephen Gottschalk, Vicky Torrano, Oumar Diouf, Stephanie Ku, Yasmin Hazrat, George Carrum, Carlos Ramos, Hao Liu, Meng-Fen Wu, Daniel Lee, Andrea M. Sheehan, Youli Zu, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Methodist Hospital; Luis Fayad, Elizabeth J. Shpall, and Barbara Pro, MD Anderson Cancer Center, Houston, TX; and Daniel Lee and Youli Zu, Weill Medical College of Cornell University, New York, NY.
出版信息
J Clin Oncol. 2014 Mar 10;32(8):798-808. doi: 10.1200/JCO.2013.51.5304. Epub 2013 Dec 16.
PURPOSE
Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33).
PATIENTS AND METHODS
These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities.
RESULTS
Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses.
CONCLUSION
Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.
目的
约 40%的霍奇金或非霍奇金淋巴瘤患者的肿瘤细胞表达 II 型潜伏 EBV（EBV）抗原潜伏膜蛋白 1（LMP1）和 LMP2，这为免疫治疗提供了有吸引力的靶点。由于针对这些抗原的 T 细胞存在频率较低，并且可能被表达它们的肿瘤使其无反应，我们使用自体树突状细胞和 EBV 转化的 B 淋巴细胞系，通过表达单独 LMP2 的腺病毒载体（n = 17）或同时表达 LMP2 和 ΔLMP1 的腺病毒载体（n = 33），从淋巴瘤患者中扩增 LMP-细胞毒性 T 淋巴细胞（CTL）。
方法
这些基因修饰的抗原呈递细胞扩增了对 II 型潜伏 LMP 抗原具有特异性的 CTL。当将扩增的 CTL 输注到 50 例 EBV 相关淋巴瘤患者中时，未产生输注毒性。
结果
在接受 LMP-CTL 作为辅助治疗的 29 例高危或多次复发患者中，28 例在 CTL 输注后中位数为 3.1 年仍处于缓解状态。没有因淋巴瘤而死亡，但有 9 例死于广泛的既往化疗和放疗相关并发症，包括心肌梗死和继发恶性肿瘤。在 CTL 输注时患有复发或耐药疾病的 21 例患者中，13 例有临床反应，包括 11 例完全缓解。在 CTL 输注后 2 个月内，可以在外周血中检测到针对 LMP 以及非病毒肿瘤相关抗原（表位扩展）的 T 细胞，但这种表位扩展的证据仅见于达到临床反应的患者中。
结论
针对 LMP2 或 LMP1 和 LMP2 抗原的自体 T 细胞可以诱导无明显毒性的持久完全缓解。它们在病程中的早期使用可能会降低延迟治疗相关死亡率。
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