Divisions of *Medical Oncology †Surgical Oncology ‡Center for Biostatistics, The Ohio State University, Columbus, OH.
J Immunother. 2014 Jan;37(1):55-62. doi: 10.1097/CJI.0000000000000009.
The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.
探讨细胞因子给药是否可以增强蛋白酶体抑制的抗肿瘤作用。研究发现，硼替佐米与干扰素-α（IFN-α）联合给药可诱导人黑素瘤细胞系协同凋亡，并延长黑素瘤小鼠模型的存活时间。进行了一项 I 期研究，以确定硼替佐米与 IFN-α-2b 联合用于转移性黑素瘤患者的耐受性和最大耐受剂量。患者按 5 周周期治疗。在第 1 周期的第 1 周，患者每周皮下接受 500 万 U/m2 的 IFN-α 三次。在第 1 周期的第 2-4 周，每周静脉注射硼替佐米，同时每周 IFN-α 三次。第 5 周有治疗间歇。第 1 周期后，硼替佐米与 IFN-α联合使用。硼替佐米以递增剂量（1.0、1.3 或 1.6 mg/m2）分 3 个队列给予 3 名患者。共治疗了 16 名患者（8 名女性，8 名男性；中位年龄 59 岁）。常见的 3 级毒性包括疲劳（5）、呕吐（3）和腹泻（3）。4 级毒性包括疲劳（3）和淋巴细胞减少症（1）。硼替佐米的最大耐受剂量为 1.3 mg/m2。1 例患者部分缓解，7 例患者疾病稳定。无进展生存期为 2.5 个月，总生存期为 10.3 个月。硼替佐米给药并未增强 IFN-α诱导循环免疫细胞中 STAT1 磷酸化的能力；然而，它确实导致促血管生成细胞因子的血浆水平降低。硼替佐米和 IFN-α的联合可以安全地用于黑素瘤患者。
