肿瘤细胞治疗研究
英文原题：Suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cell gene delivery vehicles in recurrent glioblastoma multiforme: a first-in-human, dose-escalation, phase I clinical trial.
本临床试验首次表明，使用携带 HSV-TK 基因的异体 ADSC 进行自杀基因治疗，在复发性胶质母细胞瘤患者中是安全的。
背景与目的：多形性胶质母细胞瘤（GBM）预后极差，治疗具有挑战。本研究首次在复发性 GBM 患者中评估使用携带单纯疱疹病毒-胸苷激酶（HSV-TK）基因的异体脂肪组织来源间充质干细胞（ADSC）进行自杀基因治疗的安全性。 方法：本研究为首次人体、开放标签、单臂 I 期临床试验，采用经典 3+3 剂量递增设计。纳入未接受复发手术的患者，接受该基因治疗方案。按分配剂量向肿瘤内立体定向注射 ADSC，随后给予前药 14 天。第一剂量队列（n=3）接受 2.5×10⁵ 个 ADSC；第二队列（n=3）接受 5×10⁵ 个；第三队列（n=6）接受 10×10⁵ 个。主要结局指标为干预安全性。 结果：共招募 12 例复发性 GBM 患者。中位随访 16 个月（IQR：14–18.5）。该基因治疗方案安全且耐受性良好。研究期间，11 例（91.7%）患者肿瘤进展，9 例（75.0%）死亡。总生存期（OS）中位数为 16.0 个月（95% CI：14.3–17.7），无进展生存期（PFS）中位数为 11.0 个月（95% CI：8.3–13.7）。8 例患者达到部分缓解，4 例疾病稳定。此外，体积分析、外周血细胞计数和细胞因子谱均观察到显著变化。 结论：本临床试验首次显示，携带 HSV-TK 基因的异体 ADSC 自杀基因治疗对复发性 GBM 患者安全。仍需开展多臂 II/III 期临床试验验证本研究结果，并进一步评估该方案与单独标准治疗相比的疗效。 试验注册：伊朗临床试验注册库（IRCT），IRCT20200502047277N2；注册于 2020 年 10 月 8 日。
BACKGROUND: Glioblastoma multiforme (GBM) is associated with remarkably poor prognosis, and its treatment is challenging. This investigation aimed to evaluate the safety of suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cells (ADSCs) carrying herpes simplex virus-thymidine kinase (HSV-TK) gene for the first time in patients with recurrent GBM. METHODS: This study was a first-in-human, open-label, single-arm, phase I clinical trial with a classic 3 + 3 dose escalation design. Patients who did not undergo surgery for their recurrence were included and received this gene therapy protocol. Patients received the intratumoral stereotactic injection of ADSCs according to the assigned dose followed by prodrug administration for 14 days. The first dosing cohort (n = 3) received 2.5 10 5 ADSCs; the second dosing cohort (n = 3) received 5 10 5 ADSCs; the third dosing cohort (n = 6) received 10 10 5 ADSCs. The primary outcome measure was the safety profile of the intervention. RESULTS: A total of 12 patients with recurrent GBM were recruited. The median follow-up was 16 (IQR, 14-18.5) months. This gene therapy protocol was safe and well tolerated. During the study period, eleven (91.7%) patients showed tumor progression, and nine (75.0%) died. The median overall survival (OS) was 16.0 months (95% CI 14.3-17.7) and the median progression-free survival (PFS) was 11.0 months (95% CI 8.3-13.7). A total of 8 and 4 patients showed partial response and stable disease, respectively. Moreover, significant changes were observed in volumetric analysis, peripheral blood cell counts, and cytokine profile. CONCLUSIONS: The present clinical trial, for the first time, showed that suicide gene therapy using allogeneic ADSCs carrying the HSV-TK gene is safe in patients with recurrent GBM. Future phase II/III clinical trials with multiple arms are warranted to validate our findings and further investigate the efficacy of this protocol compared with standard therapy alone. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20200502047277N2. Registered 8 October 2020, https://www.irct.ir/ .
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