本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(24)00319-2

摘要内容如下：

背景

在1期临床试验（NCT03132922）中，Afamitresgene AutoLeucel（Afami-CEL）显示出可接受的安全性和有希望的疗效。本研究的目的是进一步评估AFAMI-CEL治疗表达HLA-A*02和MAGE-A4的晚期滑膜肉瘤或黏液样圆细胞脂肪肉瘤患者的疗效。

方法

Spearhead-1是一项在加拿大、美国和欧洲的23个地点进行的开放标签、非随机、2期试验。该试验包括三个队列，本文报告了其中的主要研究队列（队列1）。队列1包括HLA-A*02患者，年龄16-75岁，患有转移性或不可切除的滑膜肉瘤或黏液样圆细胞脂肪肉瘤（经细胞遗传学证实），表达MAGE-A4，并且至少接受过一种含蒽环类药物或含异环磷酰胺的化疗。患者在淋巴细胞耗竭后接受单次静脉注射AFAMI-CEL（转导剂量范围为1.0×109-10.0×109个T细胞）。主要终点是队列1中的总体缓解率，由设盲的独立审查委员会使用实体瘤缓解评估标准（版本1.1）在改良意向治疗人群（所有接受AFAMI-CEL的患者）中进行评估。监测并报告改良意向治疗人群的不良事件，包括特别关注的不良事件（细胞因子释放综合征、长期血细胞减少和神经毒性）。该试验在ClinicalTrials.gov，NCT04044768上注册。组群1和2的招募已经结束，正在进行后续行动，组群3的招募已经开放。

调查结果

在2019年12月17日至2021年7月27日期间，52例经细胞遗传学证实的滑膜肉瘤（n=44）和黏液样圆细胞脂肪肉瘤（n=8）患者入选队列1，并接受了AFAMI-CEL治疗。患者接受了重度预处理（平均3[IQR 2至4]既往系统治疗）。中位随访时间为32.6个月（IQR 29.4~36.1）。总缓解率为37%（19/52；95%CI 24-51），滑膜肉瘤患者为39%（17/44；24-55），滑膜肉瘤患者为25%（2/8；3-65）用于粘液样圆细胞脂肪肉瘤患者。52例患者中有37例（71%）发生细胞因子释放综合征（1例3级事件）。血细胞减少是最常见的3级或更严重的不良事件（52例患者中50例[96%]出现淋巴细胞减少，44例[85%]出现中性粒细胞减少，42例[81%]出现白细胞减少）。未发生治疗相关死亡。

解释

在重度预处理的HLA-A*02和表达MAGE-A4的滑膜肉瘤患者中，AFAMI-CEL治疗产生了持久的反应。这项研究表明，T细胞受体疗法可用于有效靶向实体瘤，并为将这种方法扩展到其他实体恶性肿瘤提供了理论基础。

英文原文如下：

Abstracts

BACKGROUND  Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

METHODS  SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3.

FINDINGS  Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred.

INTERPRETATION  Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies.

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