美国H. Lee Moffitt癌症中心和研究所Benjamin C. Creelan团队取得一项新成果。他们报道了肿瘤浸润淋巴细胞(TIL) 治疗抗pd -1耐药转移性肺癌1期试验的结果。该研究成果发表在2021年8月12日出版的《自然-医学》上。

研究人员在20名接受纳武单抗单药治疗后发生进展的晚期非小细胞肺癌患者中进行了一项单臂开放标签1期试验 (NCT03215810)。主要指标是安全性，次要指标包括客观缓解率、缓解持续时间和T细胞持久性。自体TIL 来源于用白细胞介素2培养后切碎肿瘤的体外扩增。患者接受环磷酰胺和氟达拉滨去除淋巴细胞、输注TIL和白细胞介素2，随后接受纳武单抗维持治疗。根据≤17%的严重毒性发生率（95%置信区间，3-29%）的预设标准，可达到安全性指标。在13名可评估的患者中，3名确认有反应，11名患者肿瘤负荷减少，中位最佳变化为35%。两名患者在持续治疗1.5年后取得了完全缓解。

在探索性分析中，研究人员发现TIL 治疗后检测到可识别多种类型癌症突变的T细胞，并且在有反应的患者中富集。新抗原反应性T细胞克隆在治疗后外周血增殖过程中持续存在。自体TIL细胞治疗通常是安全且具有临床活性的，因此可作为转移性肺癌治疗的新策略。

据介绍，肿瘤浸润淋巴细胞过继细胞疗法已在黑色素瘤治疗中显示活性，但目前尚未有其治疗转移性非小细胞肺癌的案例。

附：英文原文

Title: Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial

Author: Creelan, Benjamin C., Wang, Chao, Teer, Jamie K., Toloza, Eric M., Yao, Jiqiang, Kim, Sungjune, Landin, Ana M., Mullinax, John E., Saller, James J., Saltos, Andreas N., Noyes, David R., Montoya, Leighann B., Curry, Wesley, Pilon-Thomas, Shari A., Chiappori, Alberto A., Tanvetyanon, Tawee, Kaye, Frederic J., Thompson, Zachary J., Yoder, Sean J., Fang, Bin, Koomen, John M., Sarnaik, Amod A., Chen, Dung-Tsa, Conejo-Garcia, Jose R., Haura, Eric B., Antonia, Scott J.

Issue&Volume: 2021-08-12

Abstract: 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.

DOI: 10.1038/s41591-021-01462-y

Source: https://www.nature.com/articles/s41591-021-01462-y