Le Cesne A, Vassal G, Farace F, Spielmann M, Le Chevalier T, Angevin E, Valteau-Couanet D, Fizazi K, Cojean I, Llombard A, Tursz T, Escudier B
Immunotherapy Unit, Institut Gustave Roussy, Villejuif, France.
J Immunother. 1999 May;22(3):268-77. doi: 10.1097/00002371-199905000-00010.
Based on the likelihood of antitumor interactions between cytokines and cytotoxic drugs, we designed a pilot study to evaluate feasibility, clinical, pharmacologic, and immunologic effects of concomitantly administered subcutaneous (SQ) recombinant interleukin-2 (r-IL-2) and doxorubicin (ADR) in patients with advanced solid tumors (AST). Patients received one injection of ADR alone (70 mg/m2) and 3 weeks later a combination of r-IL-2 (18 MIU/m2 days 1-5 s.q.) and ADR at the same dose either 3-4 h after the first r-IL-2 injection (arm 1) or 2 days after the last r-IL-2 injection (arm 2). The same combination was repeated every 4 weeks according to the evolution of the disease. Pharmacokinetics were assessed over 48 h after injection of ADR alone and after the first ADR-IL-2 cycle and immunologic monitoring at days 1 and 8 of the first ADR-IL-2 cycle. Tumors were measured at baseline, after ADR alone, and after each ADR-IL-2 cycle until progression. Twenty-one adult patients with various AST including 14 soft-tissue sarcomas (STS) entered the study, 11 in arm 1 and 10 in arm 2. All patients were heavily pretreated; 16 had received an anthracycline-containing chemotherapy regimen. Eleven patients were ADR refractory and 1 ADR resistant. Grade 4 neutropenia occurred in 28, 82, and 40% of patients after ADR alone, ADR-IL-2 in arm 1 and ADR-IL-2 in arm 2, respectively. Mucitis was higher in arm 1 (7 of 11 patients) compared with arm 2 (0 of 10) and ADR alone (0 of 21). SQ injections of r-IL-2 did not affect ADR pharmacokinetics. ADR injection in arm 1 prevented IL-2-induced lymphocyte rebounds in all patients but did not alter qualitatively non-major histocompatibility complex-restricted cytotoxicity. There was no response after ADR alone. Two patients, one in each arm, experienced a prolonged (8 and 5 months) objective response after ADR-IL-2. Both had ADR-refractory STS with a local relapse and metastatic metastases. Interestingly, both patients had unusually elevated TNF-alpha levels before and after the first ADR cycle. Combination ADR-IL-2, although toxic, is feasible and manageable with routine clinical support. r-IL-2 enhanced ADR hematologic and extrahematologic toxicities. The two objective responses observed in these heavily pretreated patients refractory to ADR supports the hypothesis of a modulation of ADR resistance, possibly mediated by means of a mechanism involving TNF-alpha. Elevated baseline TNF-alpha levels could be predictive of response to ADR-IL-2 and deserves further investigation.
基于细胞因子与细胞毒性药物之间抗肿瘤相互作用的可能性，我们设计了一项初步研究，以评估皮下注射重组白细胞介素-2（r-IL-2）与阿霉素（ADR）联合应用于晚期实体瘤（AST）患者的可行性、临床、药理学和免疫学效果。患者先单独接受一次阿霉素注射（70mg/m²），3周后接受r-IL-2（第1 - 5天皮下注射18MIU/m²）与相同剂量阿霉素的联合治疗，联合治疗中阿霉素在首次r-IL-2注射后3 - 4小时（方案1组）或最后一次r-IL-2注射后2天（方案2组）给药。根据疾病进展情况，每4周重复相同的联合治疗。在单独注射阿霉素后以及首个阿霉素 - IL-2治疗周期后48小时评估药代动力学，并在首个阿霉素 - IL-2治疗周期的第1天和第8天进行免疫学监测。在基线、单独使用阿霉素后以及每个阿霉素 - IL-2治疗周期后直至疾病进展期间测量肿瘤大小。21例患有各种AST的成年患者进入研究，其中14例为软组织肉瘤（STS），方案1组11例，方案2组10例。所有患者均经过大量预处理；16例曾接受含蒽环类药物的化疗方案。11例患者对阿霉素难治，1例对阿霉素耐药。单独使用阿霉素后、方案1组阿霉素 - IL-2治疗后以及方案2组阿霉素 - IL-2治疗后，4级中性粒细胞减少分别发生在28%、82%和40%的患者中。方案1组的粘膜炎发生率高于方案2组（11例患者中有7例）和单独使用阿霉素组（21例患者中0例）。皮下注射r-IL-2不影响阿霉素的药代动力学。方案1组注射阿霉素可防止所有患者出现IL-2诱导的淋巴细胞反弹，但未定性改变非主要组织相容性复合体限制的细胞毒性。单独使用阿霉素后无反应。两名患者，每组各一名，在接受阿霉素 - IL-2治疗后出现了延长（8个月和5个月）的客观缓解。两名患者均患有阿霉素难治性STS且伴有局部复发和远处转移。有趣的是，两名患者在首个阿霉素治疗周期前后TNF-α水平均异常升高。阿霉素 - IL-2联合治疗虽然有毒性，但在常规临床支持下是可行且可管理的。r-IL-2增强了阿霉素的血液学和血液外毒性。在这些对阿霉素难治的大量预处理患者中观察到的两个客观缓解支持了阿霉素耐药性调节的假设，可能是通过一种涉及TNF-α的机制介导的。基线TNF-α水平升高可能预测对阿霉素 - IL-2的反应，值得进一步研究。
