Hank J A, Albertini M, Wesly O H, Schiller J H, Borchert A, Moore K, Bechhofer R, Storer B, Gan J, Gambacorti C
Departments of Human Oncology, Pediatrics, and Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA.
Clin Cancer Res. 1995 May;1(5):481-91.
Anti-CD3 mAb and interleukin 2 (IL-2) were used in a Phase I study to treat 29 patients with cancer. The anti-CD3 was given as an i.v. bolus infusion over 10 min followed by two i.v. 96-h continuous infusions of IL-2 at 3 x 10(6) units/m2/day with a 3-day rest between the IL-2 infusions. Four patients were treated with 6, 18, 60, and 300 microgram/m2 anti-CD3. One patient received 3000 microgram/m2 anti-CD3. This patient developed profound hypotension and the IL-2 infusions were delayed for 2 weeks. Two patients were treated at an intermediate dose of 600 microgram/m2. These patients developed dose-limiting toxicities including hypotension, dyspnea and increased blood urea nitrogen, creatinine, and bilirubin. They were unable to complete their first course of therapy. In an effort to achieve a dose of anti-CD3 which would activate T cells in vivo, pentoxifylline was given to blunt the toxicities seen with anti-CD3 thought to be due predominantly to the cytokine syndrome and tumor necrosis factor release. Four patients received p.o. pentoxifylline to cover an anti-CD3 dose of 600 microgram/m2. The IL-2 infusion was initiated 1 week after the mAb. While there was an anti-CD3 dose-dependent increase in serum tumor necrosis factor level 1 h after mAb infusion, pentoxifylline did not reduce the serum tumor necrosis factor level. There was also an anti-CD3 dose-dependent increase in the serum soluble IL-2 receptor levels. Other immune parameters monitored, including in vitro cytotoxic and proliferative responses and lymphocyte count, were similar to treatment courses with IL-2 alone. Fourteen of 26 patients examined developed human anti-murine antibodies following a single dose of anti-CD3. There were no objective antitumor responses. We conclude that in vivo treatment with anti-CD3 did not enhance T cell activity or expansion with subsequent IL-2 infusion and that the combination of anti-CD3 followed by IL-2 did not improve upon the antitumor activity previously seen with IL-2 alone.
抗CD3单克隆抗体和白细胞介素2（IL-2）用于一项I期研究，以治疗29例癌症患者。抗CD3通过静脉推注在10分钟内输注，随后进行两次静脉96小时持续输注IL-2，剂量为3×10⁶单位/平方米/天，两次IL-2输注之间休息3天。4例患者接受了6、18、60和300微克/平方米的抗CD3治疗。1例患者接受了3000微克/平方米的抗CD3治疗。该患者出现严重低血压，IL-2输注延迟了2周。2例患者接受了600微克/平方米的中间剂量治疗。这些患者出现了剂量限制性毒性，包括低血压、呼吸困难以及血尿素氮、肌酐和胆红素升高。他们无法完成第一个疗程的治疗。为了达到能在体内激活T细胞的抗CD3剂量，给予己酮可可碱以减轻抗CD3所致的毒性，这种毒性被认为主要是由于细胞因子综合征和肿瘤坏死因子释放。4例患者口服己酮可可碱以应对600微克/平方米的抗CD3剂量。在单克隆抗体给药1周后开始输注IL-2。虽然在单克隆抗体输注1小时后血清肿瘤坏死因子水平存在抗CD3剂量依赖性升高，但己酮可可碱并未降低血清肿瘤坏死因子水平。血清可溶性IL-2受体水平也存在抗CD3剂量依赖性升高。监测的其他免疫参数，包括体外细胞毒性和增殖反应以及淋巴细胞计数，与单独使用IL-2的治疗疗程相似。26例接受检查的患者中有14例在单次给予抗CD3后产生了人抗鼠抗体。未观察到客观的抗肿瘤反应。我们得出结论，抗CD3的体内治疗并未增强T细胞活性或在随后输注IL-2时促进其扩增，并且抗CD3后接IL-2的联合治疗并未比之前单独使用IL-2时观察到的抗肿瘤活性有所改善。
