PHASE I EVALUATION OF INTERLEUKIN-1 ALPHA

INTERLEUKIN-1 ALPHA 的 I 期评估

• 批准号: 3874542
• 负责人: J W SMITH
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3874542
• 关键词: biological response modifiers; clinical trials; cytokine receptors; dosage; drug administration rate /duration; drug adverse effect; human subject; human therapy evaluation; human tissue; immunomodulators; immunotoxicity; indomethacin; interleukin 1; interleukin 6; leukocyte activation /transformation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy

Interleukin-1 (IL-1) plays a central role in immune responses and might be useful in the treatment of cancer patients for several reasons. We conducted a phase I clinical trial of IL-1 alpha to determine the: (1) toxicity of IL-1 in cancer patients, (2) effects of IL-1 in the immune system, (3) effects of IL-1 on the hemopoietic system, (4) pharmacokinetics of IL-1 and (5) the effect of adding indomethacin on all of the above. All patients had chills, fever, headache, and some had nausea, vomiting, myalgia, arthralgia, and abdominal pain. Hypotension, renal insufficiency, confusion, and abdominal pain were the dose-limiting toxicities. The inpatient-maximum tolerated dose (MTD) of IL-1 alpha administered alone with blood pressure support was determined to be 0.3 mog/kg. With the addition of indomethacin at 25 mg every 8 hours, the maximum tolerated dose was determined to be 0.1 mog/kg. IL-1 alpha did not cause an increase in peripheral blood natural killer cell and lymphokine activated killer cell activity. However, IL-1 treatment did induce increases in serum soluble IL-2 receptor levels and in IL-6 levels. Pharmacokinetic studies indicated measurable IL-1 alpha levels at the two highest dose levels consistent with a short alpha half-life of 10-15 minutes. IL-1 caused a dose related 2-7 fold increase in the white blood count (mainly increased neutrophils and neutrophil bands). The platelet count declined slightly during treatment but increased one and a half to two times above baseline one week later in five patients studied at that time. Bone marrow aspirates one day after the end of treatment showed increased cellularity and increased M/E ratio compared to ones obtained before treatment.

白细胞介素-1 (IL-1) 在免疫反应中发挥着核心作用，可能与 由于多种原因，它可用于治疗癌症患者。 我们 进行了 IL-1 α 的 I 期临床试验以确定：(1) IL-1对癌症患者的毒性，（2）IL-1对免疫的影响 系统，(3) IL-1 对造血系统的影响，(4) 药代动力学 IL-1 和 (5) 添加吲哚美辛对上述所有因素的影响。 所有患者均出现寒战、发热、头痛，部分患者出现恶心、呕吐、 肌痛、关节痛和腹痛。 低血压、肾功能不全、 意识混乱和腹痛是剂量限制性毒性。 这 单独给予 IL-1 α 的住院患者最大耐受剂量 (MTD) 在血压支持的情况下确定为0.3 mog/kg。 随着 每 8 小时添加吲哚美辛 25 mg，最大耐受剂量 测定为0.1mog/kg。 IL-1α 不会导致 外周血自然杀伤细胞和淋巴因子激活的杀伤细胞 活动。 然而，IL-1处理确实引起血清可溶性细胞因子的增加。 IL-2 受体水平和 IL-6 水平。 药代动力学研究表明 两个最高剂量水平下可测量的 IL-1 α 水平与 α 半衰期短，为 10-15 分钟。 IL-1引起剂量相关2-7 白细胞计数增加倍数（主要是中性粒细胞和 中性粒细胞带）。 治疗期间血小板计数略有下降 但一周后增加到基线的一倍半到两倍 当时有五名患者接受研究。 一天后抽取骨髓 治疗结束时细胞结构增加，M/E 比率增加 与治疗前获得的结果相比。