Sustained Complete Responses in Patients With Lymphoma Receiving Autologous Cytotoxic T Lymphocytes Targeting Epstein-Barr Virus Latent Membrane Proteins
Sustained Complete Responses in Patients With Lymphoma Receiving Autologous Cytotoxic T Lymphocytes Targeting Epstein-Barr Virus Latent Membrane Proteins
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DOI：
10.1200/jco.2013.51.5304
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发表时间：
2014-03-10
影响因子：
45.3
通讯作者：
Rooney, Cliona M.
中科院分区：
文献类型：
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作者：
Bollard, Catherine M.;Gottschalk, Stephen;Rooney, Cliona M.
目的霍奇金淋巴瘤（Hodgkin lymphoma）和非霍奇金淋巴瘤（non-Hodgkin lymphoma）患者中约40%的肿瘤细胞表达EB病毒（EBV）潜伏膜蛋白1（LMP 1）和LMP 2。因为对这些抗原特异性的T细胞以低频率存在，并且可能被表达它们的肿瘤赋予无反应性，我们使用自体树突状细胞和EBV转化的B淋巴母细胞系扩增淋巴瘤患者的LMP-细胞毒性T淋巴细胞（CTL），所述细胞系用单独表达LMP 2（n = 17）或同时表达LMP 2和LMP 1（n = 33）的腺病毒载体转导。患者和方法这些遗传修饰的抗原呈递细胞扩增了针对II型潜伏LMP抗原的特异性富集的CTL。当输注到50例EBV相关淋巴瘤患者，扩增的CTL并没有产生输注toxics.Results 28的29个高危或多次复发患者接受LMP-CTL作为辅助治疗后，在缓解中位值为3.1年CTL输注。没有人死于淋巴瘤，但有9人死于与广泛的既往放化疗相关的并发症，包括心肌梗死和继发性恶性肿瘤。在21例在CTL输注时复发或耐药的患者中，13例有临床应答，包括11例完全应答。CTL输注后2个月内可在外周血中检测到LMP特异性T细胞以及非病毒肿瘤相关抗原（表位扩散），但仅在获得临床应答的患者中观察到表位扩散的证据。结论针对LMP 2或LMP 1和LMP 2抗原的自体T细胞可诱导持久的完全应答，且无明显毒性。在病程中早期使用这些药物可降低延迟治疗相关死亡率。
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 LMP1 (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.