Ewel C H, Urba W J, Kopp W C, Smith J W, Steis R G, Rossio J L, Longo D L, Jones M J, Alvord W G, Pinsky C M
Clinical Services Program, Program Resources, Inc./DynCorp, National Cancer Institute-Frederick Cancer Research Development Center, Maryland 21702.
Cancer Res. 1992 Jun 1;52(11):3005-10.
We have performed a phase IB study of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0 mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v. by 24-h continuous infusion twice weekly, using a portable infusion pump. No objective tumor responses were observed. Toxicity was moderate at all poly-ICLC doses tested and increased only slightly following the addition of IL-2. No increases in peripheral blood natural killer (NK) activity were observed after treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than that seen using the same dose of IL-2 in combination with lower poly-ICLC doses. Increases in the number and percentage of CD56+ cells were evident only after initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the majority of patients, these increases were preferentially associated with the subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was elevated to a lesser extent. Moderate increases in serum neopterin levels and 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No induction of alpha or gamma interferon was detected. This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.
我们对25例患有各种癌症的患者进行了一项1B期研究，该研究将与聚-L-赖氨酸和羧甲基纤维素复合的聚肌苷酸-聚胞苷酸（聚ICLC）与白细胞介素2（IL-2）联合使用。患者通过肌肉注射每周或每两周接受一次聚ICLC，剂量范围为0.01至1.0mg/m²，持续1个月。之后进行2个月的门诊治疗，每两周肌肉注射聚ICLC并联合静脉注射IL-2（3×10⁶单位/m²），使用便携式输液泵每周两次进行24小时持续输注。未观察到客观的肿瘤反应。在所测试的所有聚ICLC剂量下，毒性均为中度，在添加IL-2后仅略有增加。单独使用聚ICLC治疗后未观察到外周血自然杀伤（NK）活性增加。然而，高剂量聚ICLC（大于或等于0.3mg/m²）与IL-2联合使用导致NK活性高于使用相同剂量IL-2与较低聚ICLC剂量联合使用时的活性。仅在开始IL-2治疗后，CD56⁺细胞的数量和百分比增加明显，且不受聚ICLC剂量的影响。在大多数患者中，这些增加主要与共表达CD8的CD56⁺细胞亚群相关，而CD56⁺/CD16⁺群体的升高程度较小。在初始用1.0mg/m²聚ICLC治疗72小时后，外周血单个核细胞中的血清新蝶呤水平和2',5'-寡腺苷酸合成酶活性有中度增加。未检测到α或γ干扰素的诱导。这项研究表明，在耐受性良好的IL-2方案中添加聚ICLC可显著增强NK活性。聚ICLC可用于增强IL-2诱导的NK裂解活性，而无需增加IL-2治疗的剂量，因此也不会增加其毒性。
