Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies.
Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies.
复制标题
DOI：
10.1158/1078-0432.ccr-11-1817
复制
发表时间：
2011-12-15
期刊：
影响因子：
--
通讯作者：
Wong HC
中科院分区：
文献类型：
--
作者：
Fishman MN;Thompson JA;Pennock GK;Gonzalez R;Diez LM;Daud AI;Weber JS;Huang BY;Tang S;Rhode PR;Wong HC
ALT-801 是一种双功能融合蛋白，包含与可溶性单链 T 细胞受体结构域连接的白介素 2 (IL-2)，该结构域可识别在 HLA-A*0201 (p53+/HLA-A*0201) 背景下癌细胞上展示的人 p53 抗原的肽表位 (aa264-272)。我们评估了 ALT-801 在患有转移性恶性肿瘤的 p53+/HLA-A*0201 患者中的安全性、药代动力学和药效学。 p53+/HLA-A*0201 患者接受 ALT-801 治疗，每日 4 次，每次 15 分钟静脉输注，然后休息 10 天，每日再输注 4 次。患者队列的治疗剂量为 0.015、0.040 和 0.080 mg/kg/剂量。分别有 4 名、16 名和 6 名患者接受 0.015、0.04 和 0.08 mg/kg 剂量组的治疗。 0.08 mg/kg 组中的两种剂量限制性毒性（4 级短暂性血小板减少症和心肌梗死）确定了 0.04 mg/kg 的最大耐受剂量 (MTD)。在 MTD 治疗的患者经历了与高剂量 IL-2 相关的毒性相似，但严重程度较轻。 ALT-801 的血清半衰期为 4 小时，ALT-801 血清恢复符合基于给药剂量的预期。 ALT-801 治疗诱导血清干扰素-γ 增加，但不增加肿瘤坏死因子-α。反应评估显示，10 名受试者在至少 11 周内病情稳定，其中一名患有黑色素瘤转移的受试者在切除放射学确定的病灶后，仍然完全没有可识别的疾病。这项首次人体研究定义了一种 ALT-801 治疗方案，该治疗方案可以安全给药，并且与潜在抗肿瘤相关的免疫学变化相关。
ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies. p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of 4 daily 15-minute intravenous infusions, then 10 days rest and 4 more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose. Four, sixteen, and six patients were treated at the 0.015, 0.04 and 0.08 mg/kg cohorts, respectively. Two dose limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced toxicities similar to those associated with high-dose IL-2 but of lesser severity. The serum half-life of ALT-801 was 4 hours and ALT-801 serum recovery was as expected based on the dose administered. ALT-801 treatment induced an increase of serum interferon-γ but not tumor necrosis factor-α. Response assessment showed 10 subjects with stable disease at at least 11 weeks, and in one who had melanoma metastasis, there is an ongoing complete absence of identifiable disease after resection of radiographically identified lesions. This first-in-man study defines an ALT-801 regimen that can be administered safely and is associated with immunological changes of potential antitumor relevance.