在非小细胞肺癌患者使用酪氨酸激酶抑制剂治疗失败后，联合使用 SNK01（自体自然杀伤细胞）、细胞毒性化疗药物和/或西妥昔单抗的安全性和有效性：非临床小鼠模型和 I/IIa 期临床研究。

Safety and efficacy of SNK01 (autologous natural killer cells) in combination with cytotoxic chemotherapy and/or cetuximab after failure of prior tyrosine kinase inhibitor in non-small cell lung cancer: non-clinical mouse model and phase I/IIa clinical study.

机构信息

Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mokdong Hospital, College of Medicine, Ewha Womans University, Seoul, South Korea.

出版信息

J Immunother Cancer. 2024 Mar 27;12(3):e008585. doi: 10.1136/jitc-2023-008585.

DOI:10.1136/jitc-2023-008585

PMID:38538093

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10982808/

Abstract

BACKGROUND

Choosing treatments for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with osimertinib resistance is challenging. We evaluated the safety and efficacy of SNK01 (autologous natural killer (NK) cells) in combination with cytotoxic chemotherapy and/or cetuximab (an anti-EGFR monoclonal antibody) in treating EGFR-mutated NSCLC in this non-clinical and phase I/IIa clinical trial.

METHODS

We developed a cell line-derived xenograft-humanized mouse model with an osimertinib-resistant lung cancer cell line. The mice were divided into four groups based on treatment (no treatment, cetuximab, SNK01, and combination groups) and treated weekly for 5 weeks. In the clinical study, 12 patients with EGFR-mutated NSCLC who failed prior tyrosine kinase inhibitor (TKI) received SNK01 weekly in combination with gemcitabine/carboplatin (n=6) or cetuximab/gemcitabine/carboplatin (n=6) and dose escalation of SNK01 following the "3+3" design.

RESULTS

In the non-clinical study, an increase in NK cells in the blood and enhanced NK cell tumor infiltration were observed in the SNK01 group. The volume of tumor extracted after treatment was the smallest in the combination group. In the clinical study, 12 patients (median age, 60.9 years; all adenocarcinoma cases) received SNK01 weekly for 7-8 weeks (4×10 cells/dose (n=6); 6×10 cells/dose (n=6)). The maximum feasible dose of SNK01 was 6×10 cells/dose without dose-limiting toxicity. Efficacy outcomes showed an objective response rate of 25%, disease control rate of 100%, and median progression-free survival of 143 days.

CONCLUSION

SNK01 in combination with cytotoxic chemotherapy, including cetuximab, for EGFR-mutated NSCLC with TKI resistance was safe and exerted a potential antitumor effect.

TRIAL REGISTRATION NUMBER

NCT04872634.

摘要

背景

对于表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者出现奥希替尼耐药时，选择治疗方法具有挑战性。我们在这项非临床和 I/IIa 期临床试验中评估了 SNK01（自体自然杀伤（NK）细胞）联合细胞毒性化疗和/或西妥昔单抗（一种抗 EGFR 单克隆抗体）治疗 EGFR 突变型 NSCLC 的安全性和疗效。

方法

我们开发了一种细胞系衍生的异种移植-人源化小鼠模型，该模型使用奥希替尼耐药的肺癌细胞系。根据治疗方法（无治疗、西妥昔单抗、SNK01 和联合组）将小鼠分为四组，并每周治疗 5 周。在临床研究中，12 名先前接受酪氨酸激酶抑制剂（TKI）治疗失败的 EGFR 突变型 NSCLC 患者每周接受 SNK01 联合吉西他滨/卡铂（n=6）或西妥昔单抗/吉西他滨/卡铂（n=6）治疗，并根据“3+3”设计进行 SNK01 的剂量递增。

结果

在非临床研究中，SNK01 组的血液 NK 细胞增加，NK 细胞肿瘤浸润增强。治疗后提取的肿瘤体积在联合组中最小。在临床研究中，12 名患者（中位年龄 60.9 岁；均为腺癌病例）每周接受 SNK01 治疗 7-8 周（4×10 个细胞/剂量（n=6）；6×10 个细胞/剂量（n=6））。SNK01 的最大可行剂量为 6×10 个细胞/剂量，无剂量限制性毒性。疗效结果显示客观缓解率为 25%，疾病控制率为 100%，中位无进展生存期为 143 天。