Department of Medicine, University of Louisville, Louisville, Kentucky, USA.
Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA.
J Immunother Cancer. 2022 Dec;10(12). doi: 10.1136/jitc-2022-005755.
Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma.
Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1).
The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD <median had greater likelihood of response than those with either (OR=2.08) or both (OR=4.42) risk factors. The most common grade 3/4 treatment-emergent adverse events (≥30%) were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%).
Investigational lifileucel demonstrated clinically meaningful activity in heavily pretreated patients with advanced melanoma and high tumor burden. Durable responses and a favorable safety profile support the potential benefit of one-time lifileucel TIL cell therapy in patients with limited treatment options in ICI-refractory disease.
在免疫检查点抑制剂（ICI）进展后，晚期黑色素瘤患者的治疗选择有限。lifileucel 是一种一次性自体肿瘤浸润淋巴细胞（TIL）细胞疗法，在 66 名接受 ICI 和靶向治疗后进展的患者中，研究者评估的客观缓解率（ORR）为 36%。在此，我们报告了在一项大型多中心黑色素瘤 2 期细胞治疗试验中，153 名接受 lifileucel 治疗的患者经独立审查委员会（IRC）评估的结果。
符合条件的患者为晚期黑色素瘤，在接受 ICI 和靶向治疗后进展，如有必要。切除黑色素瘤病变（切除肿瘤直径≥1.5cm）并运送到中央良好生产规范设施进行 22 天 lifileucel 制造。患者接受非清髓性淋巴细胞耗竭方案、单次 lifileucel 输注和最多六剂高剂量白细胞介素-2。主要终点是 IRC 评估的 ORR（实体瘤反应评估标准 V.1.1）。
全分析集包括 153 名接受 lifileucel 治疗的患者，包括先前报告的 66 名患者的更长随访。患者接受了中位数为 3.0 线的先前治疗（81.7%同时接受抗程序性细胞死亡蛋白 1 和抗细胞毒性淋巴细胞相关蛋白 4 治疗），基线时疾病负担较高（中位靶病变总和直径（SOD）：97.8mm；乳酸脱氢酶（LDH）>正常值上限：54.2%）。ORR 为 31.4%（95%CI：24.1%至 39.4%），8 例完全缓解和 40 例部分缓解。在中位数为 27.6 个月的中位研究随访中，中位缓解持续时间未达到，41.7%的缓解持续时间≥18 个月。中位总生存期和无进展生存期分别为 13.9 个月和 4.1 个月。多变量分析调整东部合作肿瘤学组表现状态后，结果表明升高的 LDH 和靶病变 SOD>中位数与 ORR 独立相关（p=0.008）；LDH 和 SOD<中位数正常的患者比两者（OR=2.08）或两者（OR=4.42）均有更高的缓解可能性。最常见的 3/4 级治疗相关不良事件（≥30%）为血小板减少症（76.9%）、贫血（50.0%）和发热性中性粒细胞减少症（41.7%）。
研究性 lifileucel 在晚期黑色素瘤和高肿瘤负荷的大量预处理患者中表现出了有临床意义的活性。持久的缓解和有利的安全性特征支持一次性 lifileucel TIL 细胞疗法在 ICI 难治性疾病中治疗选择有限的患者中的潜在获益。
