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Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma
Journal of Clinical Oncology ( IF 45.3 ) Pub Date : 2018-04-10 , DOI: 10.1200/jco.2017.74.3179
Catherine M Bollard 1 , Tamara Tripic 1 , Conrad Russell Cruz 1 , Gianpietro Dotti 1 , Stephen Gottschalk 1 , Vicky Torrano 1 , Olga Dakhova 1 , George Carrum 1 , Carlos A Ramos 1 , Hao Liu 1 , Meng-Fen Wu 1 , Andrea N Marcogliese 1 , Cecilia Barese 1 , Youli Zu 1 , Daniel Y Lee 1 , Owen O'Connor 1 , Adrian P Gee 1 , Malcolm K Brenner 1 , Helen E Heslop 1 , Cliona M Rooney 1
Affiliation  

Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus-positive Hodgkin lymphoma received two to 12 doses of between 2 × 107 and 1.5 × 108 cells/m2 of DNRII-expressing T cells with specificity for the Epstein Barr virus-derived tumor antigens, latent membrane protein (LMP)-1 and LMP-2 (DNRII-LSTs). Lymphodepleting chemotherapy was not used before infusion. Results DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their tumor antigen-specific activity. After infusion, the signal from transgenic T cells in peripheral blood increased up to 100-fold as measured by quantitative polymerase chain reaction for the transgene, with a corresponding increase in the frequency of functional LMP-specific T cells. Expansion was not associated with any acute or long-term toxicity. DNRII-LSTs persisted for up to ≥ 4 years. Four of the seven evaluable patients with active disease achieved clinical responses that were complete and ongoing in two patients at > 4 years, including in one patient who achieved only a partial response to unmodified tumor-directed T cells. Conclusion TGF-β-resistant tumor-specific T cells safely expand and persist in patients with Hodgkin lymphoma without lymphodepleting chemotherapy before infusion. DNRII-LSTs can induce complete responses even in patients with resistant disease. Expression of DNRII may be useful for the many other tumors that exploit this potent immune evasion mechanism.

中文翻译:

为克服肿瘤免疫逃避而设计的肿瘤特异性 T 细胞可诱导复发性霍奇金淋巴瘤患者的临床反应

目的 肿瘤微环境中转化生长因子-β (TGF-β) 的产生是一种有效且普遍存在的肿瘤免疫逃避机制,可抑制肿瘤定向反应的扩展和功能;因此,我们进行了一项临床研究,以发现强制表达 2 型显性阴性 TGF-β 受体 (DNRII) 对输注的肿瘤导向 T 细胞的安全性、存活率和活性的影响。材料和方法 在剂量递增研究中,8 名 Epstein Barr 病毒阳性霍奇金淋巴瘤患者接受了 2 到 12 剂 2 × 107 和 1.5 × 108 个细胞/m2 表达 DNRII 的具有 Epstein Barr 病毒特异性的 T 细胞-衍生的肿瘤抗原,潜膜蛋白 (LMP)-1 和 LMP-2 (DNRII-LSTs)。输注前未使用淋巴细胞清除化疗。结果 DNRII-LST 在体外对其他抑制浓度的 TGF-β 具有抗性,并保持其肿瘤抗原特异性活性。输注后,外周血中转基因 T 细胞的信号增加了 100 倍,如通过转基因的定量聚合酶链反应测量的那样,功能性 LMP 特异性 T 细胞的频率相应增加。扩张与任何急性或长期毒性无关。DNRII-LST 持续时间长达 ≥ 4 年。7 名可评估的活动性疾病患者中有 4 名获得了完全且持续的临床反应,其中两名患者在 > 4 年时,包括一名对未修饰的肿瘤定向 T 细胞仅获得部分反应的患者。结论 TGF-β 耐药的肿瘤特异性 T 细胞在输注前无需进行淋巴耗竭化疗的霍奇金淋巴瘤患者中可安全扩增并持续存在。DNRII-LSTs 甚至可以在耐药患者中诱导完全反应。DNRII 的表达可能对利用这种有效免疫逃避机制的许多其他肿瘤有用。
更新日期:2018-04-10
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