Department of Medicine, Division of Hematology/Oncology, Lymphoma Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
J Immunother. 2013 Jul-Aug;36(6):331-41. doi: 10.1097/CJI.0b013e31829d7e2e.
Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3-4 patients were given infusions of rituximab (375 mg/m2) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B-cell non-Hodgkin lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 μg/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, GM-CSF, and chemokines were observed after dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.
白细胞介素-18（IL-18）是一种具有免疫刺激活性的细胞因子，在临床前模型中具有抗肿瘤活性。利妥昔单抗是一种针对人类 B 细胞淋巴瘤的 CD20 单克隆抗体。在 CD20+淋巴瘤患者中进行了重组人（rh）IL-18 与利妥昔单抗联合应用的 I 期研究。3-4 名患者为一组，每周静脉滴注利妥昔单抗（375mg/m2）共 4 周，同时每周静脉滴注 rhIL-18 12 周，剂量逐渐递增。毒性采用标准标准分级。采集血样进行安全性、药代动力学和药效学研究。19 例 CD20+B 细胞非霍奇金淋巴瘤患者接受利妥昔单抗联合 rhIL-18 治疗，剂量分别为 1、3、10、20、30 和 100μg/kg。常见的副作用包括寒战、发热、头痛和恶心。常见的实验室异常包括一过性无症状性淋巴细胞减少、高血糖、贫血、低白蛋白血症、胆红素和肝酶升高。未观察到剂量限制性毒性。rhIL-18 的生物学效应包括一过性淋巴细胞减少和淋巴细胞激活抗原表达增加。给药后观察到血清 IFN-γ、GM-CSF 和趋化因子浓度增加。5 例患者出现客观肿瘤反应，包括 2 例完全缓解和 3 例部分缓解。rhIL-18 可与利妥昔单抗联合每周输注，以生物活性剂量给予淋巴瘤患者。未确定 rhIL-18 联合利妥昔单抗的最大耐受剂量。进一步研究 rhIL-18 和 CD20 单克隆抗体在 B 细胞恶性肿瘤中的作用是必要的。
