Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Lancet Oncol. 2017 Jun;18(6):792-802. doi: 10.1016/S1470-2045(17)30251-6. Epub 2017 Apr 7.
Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma.
In this ongoing single-centre, two-stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide [60 mg/kg] daily for 2 days followed by fludarabine [25 mg/m] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 [720 000 IU/kg] every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. The trial is registered at ClinicalTrials.gov, number NCT01814046.
From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16-59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure.
To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality.
Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
葡萄膜黑色素瘤是一种罕见的肿瘤，一旦发生转移，目前尚无既定的治疗方法。虽然多种基于免疫的疗法在转移性皮肤黑色素瘤中显示出疗效，但在眼部变异型中的应用令人失望。最近，过继性 T 细胞疗法在多种难治性实体瘤中显示出挽救反应。因此，我们试图确定过继转移自体肿瘤浸润淋巴细胞（TIL）是否可以介导转移性葡萄膜黑色素瘤的消退。
在这项正在进行的单中心、两阶段、2 期、单臂试验中，招募了经组织学证实患有转移性眼内黑色素瘤的患者（年龄≥16 岁）。主要入选标准为东部合作肿瘤学组（ECOG）表现状态为 0 或 1、进行性转移性疾病以及足够的血液学、肾脏和肝功能。进行转移性切除术以获取肿瘤组织来生成自体 TIL 培养物，然后对其进行大规模体外扩增。患者接受淋巴耗竭预处理化疗（环磷酰胺[60mg/kg]每日静脉注射 2 天，随后氟达拉滨[25mg/m]每日静脉注射 5 天，随后单次静脉输注自体 TIL 和高剂量白细胞介素-2[720000IU/kg]每 8 小时）。主要终点是根据实体瘤反应评价标准 1.0（Response to Evaluation Criteria in Solid Tumors, version 1.0）对可评估患者的客观肿瘤反应。这里报告了该试验的中期分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT01814046。
从该试验的第一阶段和正在进行的扩展阶段中，2013 年 6 月 7 日至 2016 年 9 月 9 日期间共招募了 21 例转移性葡萄膜黑色素瘤患者，并接受了 TIL 治疗。20 例可评估患者中，有 7 例（35%，95%CI 16-59）有客观肿瘤消退。在应答者中，6 例患者获得部分缓解，其中 2 例仍在进行中，尚未达到最大缓解。1 例患者获得了许多肝转移的完全缓解，目前在治疗后 21 个月仍在持续。3 名应答者对先前的免疫检查点阻断有耐药性。常见的 3 级或更高级别的毒性与淋巴耗竭化疗方案有关，包括淋巴细胞减少、中性粒细胞减少和血小板减少（每种毒性均为 21[100%]例患者）；贫血（14[67%]例患者）；和感染（6[29%]例患者）。有一例与脓毒症引起的多器官衰竭相关的治疗相关死亡。
据我们所知，这是首例描述过继转移自体 TIL 介导转移性葡萄膜黑色素瘤患者客观肿瘤消退的报告。这些初步结果挑战了转移性葡萄膜黑色素瘤对免疫治疗有抵抗力的观点，并支持进一步研究这种癌症的免疫治疗方法。为了提高临床反应的频率和这种治疗方式的普遍适用性，对这种 T 细胞疗法进行改进至关重要。
美国国立卫生研究院、国家癌症研究所、癌症研究中心内部研究计划。
