Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown activity in melanoma, but has not been previously evaluated in metastatic non-small cell lung cancer. We conducted a single-arm open-label phase 1 trial (NCT03215810) of TILs administered with nivolumab in 20 patients with advanced non-small cell lung cancer following initial progression on nivolumab monotherapy. The primary end point was safety and secondary end points included objective response rate, duration of response and T cell persistence. Autologous TILs were expanded ex vivo from minced tumors cultured with interleukin-2. Patients received cyclophosphamide and fludarabine lymphodepletion, TIL infusion and interleukin-2, followed by maintenance nivolumab. The end point of safety was met according to the prespecified criteria of ≤17% rate of severe toxicity (95% confidence interval, 3–29%). Of 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses that were ongoing 1.5 years later. In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in responding patients. Neoantigen-reactive T cell clonotypes increased and persisted in peripheral blood after treatment. Cell therapy with autologous TILs is generally safe and clinically active and may constitute a new treatment strategy in metastatic lung cancer.

使用肿瘤浸润淋巴细胞 (TIL) 的过继细胞疗法已在黑色素瘤中显示出活性，但之前尚未在转移性非小细胞肺癌中进行评估。我们对 20 名晚期非小细胞肺癌患者进行了一项单组开放标签 1 期试验 (NCT03215810)，在接受纳武单抗单药治疗后出现初步进展后，给予 TIL 联合纳武单抗治疗。主要终点是安全性，次要终点包括客观缓解率、缓解持续时间和 T 细胞持久性。自体 TIL 是从用白细胞介素 2 培养的切碎肿瘤离体扩增的。患者接受环磷酰胺和氟达拉滨淋巴清除、TIL 输注和白细胞介素 2，然后接受纳武单抗维持治疗。根据严重毒性发生率≤17%（95%置信区间，3-29%）的预设标准，达到了安全终点。在 13 名可评估的患者中，3 名已确认缓解，11 名肿瘤负荷减少，中位最佳变化为 35%。两名患者获得了完全缓解，这种缓解持续了 1.5 年后。在探索性分析中，我们发现 TIL 治疗后检测到识别多种癌症突变的 T 细胞，并且在有反应的患者中富集。治疗后外周血中新抗原反应性 T 细胞克隆型增加并持续存在。自体 TIL 细胞疗法通常是安全的且具有临床活性，可能构成转移性肺癌的新治疗策略。