背景:Afamitresgeneautoleucel(afami-cel)在1期试验(NCT03132922)中显示出可接受的安全性和有希望的疗效。这项研究的目的是进一步评估afami-cel治疗HLA-A*02和MAGE-A4表达的晚期滑膜肉瘤或粘液样圆形细胞脂肪肉瘤的疗效。
方法:SPEARHEAD-1是开放标签,非随机化,在加拿大23个地点进行的第二阶段试验,美国,和欧洲。该试验包括三个队列,其中主要研究队列(队列1)在此报告。队列1包括HLA-A*02患者,年龄16-75岁,患有表达MAGE-A4的转移性或不可切除的滑膜肉瘤或粘液样圆形细胞脂肪肉瘤(通过细胞遗传学证实),并且先前接受过至少一种含蒽环类或含异环磷酰胺的化疗。淋巴清除后,患者接受了单次静脉内剂量的afami-cel(转导的剂量范围为1·0×109-10·0×109T细胞)。主要终点是队列1的总体缓解率,由一个隐蔽的独立审查委员会使用改良的意向治疗人群(所有接受afami-cel的患者)中实体瘤的反应评估标准(1.1版)进行评估。不良事件,包括那些特别感兴趣的(细胞因子释放综合征,延长的血细胞减少症,和神经毒性),进行监测,并报告修改后的意向治疗人群。该试验在ClinicalTrials.gov注册,NCT04044768;队列1和2的招募已结束,正在进行随访,队列3的招募已开放。
结果:在2019年12月17日至2021年7月27日之间,纳入了52例细胞遗传学证实的滑膜肉瘤(n=44)和粘液样圆形细胞脂肪肉瘤(n=8)患者,并在队列1中接受了afami-cel。患者进行了大量的预处理(中位数为3[IQR2至4]之前的全身治疗线)。中位随访时间为32·6个月(IQR29·4-36·1)。总体缓解率为37%(52人中的19人;95%CI24-51),39%(44人中的17人;24-55)用于滑膜肉瘤患者,黏液样圆形细胞脂肪肉瘤患者占25%(八分之二;3-65)。52例患者中有37例(71%)发生了细胞因子释放综合征(1例3级事件)。细胞减少症是最常见的3级或更严重的不良事件(50例[96%]淋巴细胞减少症,中性粒细胞减少症44[85%],52例患者中的白细胞减少症42例[81%])。无治疗相关死亡发生。
结论:Afami-cel治疗导致严重预处理的HLA-A*02和MAGE-A4表达滑膜肉瘤患者的持续反应。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。
背景:Adaptimmune。
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Adaptimmune.