Eom Hyeon-Seok, Choi Beom K, Lee Youngjoo, Lee Hyewon, Yun Tak, Kim Young H, Lee Je-Jung, Kwon Byoung S
*Hematologic Oncology Clinic, Center for Specific Organs Cancer, National Cancer Center, Korea †Center for Clinical Trial, National Cancer Center, Korea ‡Cancer Immunology Branch, Division of Cancer Biology §Immune Cell Production Unit, Program for Immunotherapeutic Research, Research Institute and Hospital, National Cancer Center, Ilsandong-gu, Goyang, Gyeonggi ∥Department of Hematology-Oncology, Chonnam National University Medical School, Gwangju, Korea ¶Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA.
J Immunother. 2016 Apr;39(3):140-8. doi: 10.1097/CJI.0000000000000113.
Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8 T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon-γ response: 1 approximately 1 week and the other 4-8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy.
尽管使用抗原特异性T细胞的过继性细胞疗法已在临床上成功进行了测试，但这些T细胞的生产一直具有挑战性。通过应用我们简单实用的基于4-1BB的方法来生成抗原特异性CD8 T细胞，我们在此确定了复发/难治性EB病毒（EBV）阳性肿瘤患者中自体EBV/LMP2A特异性CD8 T细胞（EBV诱导的天然T细胞；EBViNT）的最大耐受剂量、毒性特征、免疫反应和临床疗效。这是一项单中心、I期、剂量递增试验研究，评估单次注射EBViNT的4种递增给药方案。确定了每位患者针对不同LMP2A肽的CD8 T细胞反应，并使用最有效的肽来生产EBViNT。将产生的自体EBViNT单次输注给对标准治疗无效且为HLA-A02或A24型的EBV相关恶性肿瘤患者。在纳入的11名患者中，8名患者接受了单次EBViNT输注：4例为鼻咽癌，1例为霍奇金淋巴瘤，2例为结外NK/T淋巴瘤，1例为弥漫性大B细胞淋巴瘤。所有患者对单次EBViNT输注耐受性良好，其中3例产生了客观抗肿瘤反应。EBViNT输注诱导了两波干扰素-γ反应：一波在治疗后约1周，另一波在治疗后4-8周。第二波的强度与治疗效果相关。当前试验表明，EBViNT疗法是安全的，可能为治疗对传统疗法耐药的EBV阳性复发性癌症患者提供新的选择。
