Sosman J A, Kefer C, Fisher R I, Jacobs C D, Pumfery P, Ellis T M
Division of Hematology/Oncology, Loyola University Medical Center, Maywood, IL 60153, USA.
J Immunother Emphasis Tumor Immunol. 1995 Apr;17(3):171-80. doi: 10.1097/00002371-199504000-00006.
Preclinical studies have shown that anti-CD3 antibodies can enhance the in vitro activation of human T lymphocytes in combination with low-dose interleukin-2 (IL-2) and induce the in vivo rejection of murine tumors. A Phase IA/IB trial combining a murine monoclonal antibody, anti-CD3 antibody (OKT3), with low-dose continuous-infusion IL-2 was conducted in cancer patients to define the toxicity and immunologic effects of this combination. OKT3 administered weekly as a 15-min infusion at dose levels of 10, 100, 200, 400, and 600 micrograms/m2 was followed 18 h later by a 100-h infusion of IL-2 at 3 MIU/m2/day for 3 consecutive weeks. When feasible, patients also received the IL-2 course without OKT3 to assess the effects of OKT3 on the IL-2 regimen within the same patient. Thirty patients were enrolled onto the study, with 24 completing the OKT3/IL-2 course and 18 completing both OKT3/IL-2 and IL-2 alone courses. OKT3 administration was associated with acute hypotension with fevers of > 40 degrees C and in two patients cerebral vascular infarcts. At 600 micrograms/m2 OKT3, these toxicities were dose limiting. In a dose-dependent manner, OKT3 induced the transient release of tumor necrosis factor (TNF) and IL-6 into the serum and a profound lymphopenia. OKT3 did not significantly enhance the toxicity of this schedule of IL-2 administration. All solid tumor patients treated at 100-600 micrograms/m2 OKT3 showed induction of a human anti-murine antibody response prior to the third week of treatment. A patient with renal cell cancer treated at the 600-micrograms/m2 OKT3 dose level experienced a 4-month partial remission, and two mixed responses were observed in a sarcoma and a melanoma patient treated at 100- and 400-micrograms/m2 OKT3 dose levels, respectively. Most importantly, we were unable to demonstrate that the addition of OKT3 enhanced immune activation within peripheral blood based upon the magnitude of rebound lymphocytosis, increase in CD56+ or CD3+, CD25+ lymphocytes, induction of natural killer, lymphokine activated killer, or cytolytic T lymphocyte cytotoxicity, or release of serum cytokines (TNF, IL-6) or soluble CD25 (as assayed 24 h following IL-2 infusion). Therefore, this approach was ineffective at enhancing the immunologic effects of a low-dose continuous-infusion IL-2 regimen and will not be pursued further in clinical trials.
临床前研究表明，抗CD3抗体与低剂量白细胞介素-2（IL-2）联合使用时，可增强人T淋巴细胞的体外激活，并诱导小鼠肿瘤在体内被排斥。在癌症患者中进行了一项IA/IB期试验，将鼠单克隆抗体抗CD3抗体（OKT3）与低剂量持续输注IL-2联合使用，以确定该联合用药的毒性和免疫效应。OKT3每周给药一次，以15分钟输注的方式给予，剂量水平分别为10、100、200、400和600微克/平方米，18小时后接着以3 MIU/平方米/天的剂量连续100小时输注IL-2，共持续3周。在可行的情况下，患者还接受了不含OKT3的IL-2疗程，以评估OKT3对同一患者IL-2治疗方案的影响。30名患者入组该研究，其中24名完成了OKT3/IL-2疗程，18名完成了OKT3/IL-2和单独的IL-2疗程。给予OKT3与急性低血压以及体温高于40摄氏度相关，且有两名患者发生了脑血管梗死。在OKT3剂量为600微克/平方米时，这些毒性成为剂量限制性毒性。OKT3以剂量依赖性方式诱导肿瘤坏死因子（TNF）和IL-6短暂释放到血清中，并导致严重的淋巴细胞减少。OKT3并未显著增强这种IL-2给药方案的毒性。所有接受100 - 600微克/平方米OKT3治疗的实体瘤患者在治疗第三周前均出现了人抗鼠抗体反应。一名接受600微克/平方米OKT3剂量水平治疗的肾细胞癌患者经历了4个月的部分缓解，在分别接受100微克/平方米和400微克/平方米OKT3剂量水平治疗的一名肉瘤患者和一名黑色素瘤患者中观察到了两种混合反应。最重要的是，基于淋巴细胞增多反弹的幅度、CD56 +或CD3 +、CD25 +淋巴细胞的增加、自然杀伤细胞、淋巴因子激活的杀伤细胞或细胞毒性T淋巴细胞细胞毒性的诱导，或血清细胞因子（TNF、IL-6）或可溶性CD25的释放（在IL-2输注后24小时检测），我们无法证明添加OKT3能增强外周血中的免疫激活。因此，这种方法在增强低剂量持续输注IL-2方案的免疫效应方面无效，不会在临床试验中进一步探索。
