Altan Mehmet, Lopes Gilberto, Hiltermann T Jeroen N, Govindan Ramaswamy, Villaruz Liza C, Calvo Emiliano, Edelman Martin J, Furqan Muhammad, Neal Joel, Felip Enriqueta, Carlisle Jennifer W, Heymach John V, O'Cearbhaill Róisín Eilish, Zauderer Marjorie, Chisamore Michael, Corigliano Ellie, Eleftheriadou Ioanna, Zajic Stefan, Jenkins Ben, Goodison Sophia, Suchindran Sunil, Ramos-Hernandez Natalia, Tarek Nidale, Schoenfeld Adam J
Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
University of Miami Health System, Miami, Florida.
Clin Cancer Res. 2025 Feb 3;31(3):529-542. doi: 10.1158/1078-0432.CCR-24-1591.
The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A02-positive (HLA-A02:01, HLA-A02:05, and/or HLA-A02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.
Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer.
More than 2,500 patients were screened for target expression. In the multiarm study, 738 (45%) of 1,638 tested patients were HLA-A02-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-A02 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 (AE) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not seem to increase toxicity over lete-cel alone. Limited antitumor 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.
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. Antitumor activity was observed in a limited number of patients.
本研究旨在评估在HLA - A02阳性（HLA - A02:01、HLA - A02:05和/或HLA - A02:06）的NY - ESO - 1和/或LAGE - 1a阳性非小细胞肺癌患者中，单独使用或与帕博利珠单抗联合使用来替雷利尤基因自体T细胞（lete - cel，表达针对纽约食管鳞状细胞癌1（NY - ESO - 1）/LAGE - 1a共享表位的T细胞受体的基因改造自体T细胞）的安全性、耐受性和抗肿瘤反应。
研究208749是一项单独使用lete - cel的单臂研究。研究208471是一项针对晚期或复发性非小细胞肺癌患者单独使用lete - cel或与帕博利珠单抗联合使用的多臂研究。
超过2500名患者接受了靶标表达筛查。在多臂研究中，1638名受试患者中有738名（45%）为HLA - A02阳性。受试患者中，NY - ESO - 1和LAGE - 1a检测呈阳性的分别占12%（62/525）和4%（15/348）。在单臂研究中，筛选出41名HLA - A02和抗原表达阳性的患者。总体而言，43名患者接受了白细胞分离术，两项研究共有18名患者接受了lete - cel治疗。Lete - cel显示出可控的安全性。两项研究均未报告与治疗相关的致命严重不良事件（AE）。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。将帕博利珠单抗与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名患者中有1名有持续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。
进行了广泛的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，未出现意外的AE。在少数患者中观察到了抗肿瘤活性。
