PHASE I TRIAL OF ANTI-CD3 MONOCLONAL ANTIBODIES IN PATIENTS WITH ADVANCED CANCER

我们在患者中进行了一项抗CD 3单克隆抗体的I期研究， 以确定毒性和免疫调节特性 这种抗体的不同剂量和时间表 首先，协议 设计用于以六种剂量水平之一治疗五名患者， 10、30、100、300和1，000微克（mog）/患者。 患者接受 两周内三小时输注四次。 剂量限制性毒性 在100 mog抗CD 3和进一步剂量下，所有3例患者均发生了 停止升级。 剂量限制性毒性包括严重的 与无菌性脑膜炎综合征有关头痛。 脑脊髓 液体显示异常淋巴细胞增多伴蛋白质升高。 因此 通过3小时输注的抗-CD 3的最大耐受剂量为30 μ g。 一个 另外5名患者接受了30 mog的快速推注， 同样的免疫学数据没有显示出明显的变化， schedule. 由于缺乏免疫作用的毒性， 根据该时间表给予抗CD 3，我们改为每日一次 给药14天。 我们治疗了五个病人， 抗CD 3单次推注两次三小时输注 出现严重头痛 2例接受3 mog 3小时输注的患者和1/5例患者 接受推注给药。 毒性似乎与 剂量、输注持续时间和抗CD 3给药频率。

We undertook a Phase I study of anti-CD3 monoclonal antibodies in patients with solid tumors to determine the toxicity and immunomodulatory properties of this antibody at various doses and schedules. Initially, the protocol was designed to treat five patients at one of six dose levels including 1, 10, 30, 100, 300 and 1,000 micrograms (mog) per patient. Patients received four doses by three-hour infusion over two weeks. Dose-limiting toxicity occurred in all three patients at 100 mog of anti-CD3 and further dose escalation was discontinued. Dose-limiting toxicity consisted of severe headache associated with a syndrome of aseptic meningitis. Cerebrospinal fluid showed an abnormal lymphocytosis with an elevated protein. Thus, the maximum tolerated dose of anti-CD3 by three-hour infusion was 30 mog. An additional five patients received 30 mog by bolus injection according to the same immunologic data failed to reveal marked changes according to this schedule. Because of the toxicity at lack of immunologic effects when anti-CD3 is administered according to this schedule, we changed to daily administration for 14 days. We treated five patients with three mog of anti-CD3 by bolus and two by three-hour infusion. Severe headache was seen in both patients receiving 3 mog by three-hour infusion and in 1/5 patients receiving bolus administration. Toxicity appears to be related to the dose, duration of infusion and frequency of anti-CD3 administration.