Purpose: To evaluate safety, tolerability, and anti-tumor response of lete-cel, genetically modified autologous T-cells expressing a T-cell receptor specific for NY-ESO-1/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in human leukocyte antigen HLA-A*02-positive (HLA-A*02:01-, HLA-A*02:05-, and/or HLA-A*02:06-) patients with New York esophageal squamous cell carcinoma 1 (NY-ESO-1)- and/or LAGE-1a-positive non-small cell lung cancer (NSCLC). Experimental Design: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multi-arm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent NSCLC. Results: Over 2500 patients were screened for target expression. In the multi-arm study, 738 (45%) of 1638 tested patients were HLA-A*02-positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AEs) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not appear to increase toxicity over lete-cel alone. Limited anti-tumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients. Conclusions: Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Anti-tumor activity was observed in a limited number of patients.

中文翻译：

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Letetresgene Autoleucel （Lete-cel;GSK3377794）：晚期非小细胞肺癌患者的初步研究


目的：评估表达 NY-ESO-1/LAGE-1a 共享表位特异性 T 细胞受体的转基因自体 T 细胞在纽约食管鳞状细胞癌 1 （NY-ESO-1） 和/或 LAGE-1a 阳性非小细胞肺癌 （NSCLC） 人白细胞抗原 HLA-A*02：01-、HLA-A*02：05-和/或 HLA-A*02：06-） 患者中的安全性、耐受性和抗肿瘤反应。实验设计： 研究 208749 是一项单独使用 lete-cel 的单臂研究。研究208471是一项多臂研究，将 lete-cel 单独使用或与 pembrolizumab 联合治疗晚期或复发性 NSCLC 患者。结果： 筛选了 2500 多例患者的靶标表达。在这项多组研究中，1638 名受检患者中有 738 名 （45%） 为 HLA-A*02 阳性。NY-ESO-1 和 LAGE-1a 检测分别在 12% （62/525） 和 4% （15/348） 的受测患者中呈阳性。在单臂研究中筛选了 41 例 HLA-A*02 和抗原表达阳性患者。总体而言，在研究中，43 例患者接受了白细胞去除术，18 例接受了 lete-cel。Lete-cel 表现出可控的安全性。两项研究均未报告致命的治疗相关严重不良事件 （AEs）。血细胞减少和细胞因子释放综合征是最常见的治疗中出现的 AE。帕博利珠单抗与 lete-cel 联合使用似乎不会比单独使用 lete-cel 增加毒性。观察到有限的抗肿瘤活性;18 例患者中有 1 例持续 18 个月的持久反应。药代动力学数据显示所有患者的 T 细胞扩增相似。结论： 进行广泛的 HLA-A*02 和抗原表达检测以确定潜在参与者。Lete-cel 总体耐受性良好，无意外 AE。 在有限数量的患者中观察到抗肿瘤活性。