Sosman Jeffrey A, Carrillo Carole, Urba Walter J, Flaherty Lawrence, Atkins Michael B, Clark Joseph I, Dutcher Janet, Margolin Kim A, Mier James, Gollob Jarod, Kirkwood John M, Panka David J, Crosby Nancy A, O'Boyle Kevin, LaFleur Bonnie, Ernstoff Marc S
Vanderbilt-Ingram Cancer Center Vanderbilt, University Medical Center, Section of Hematology/Oncology, 777 Preston Research Bldg, Nashville, TN 37232-6307, USA.
J Clin Oncol. 2008 May 10;26(14):2292-8. doi: 10.1200/JCO.2007.13.3165.
High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2-restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial.
In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment.
From 1998 to 2003, 131 patients with HLA-A2-positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at >or= 30 months. Immune studies including assays of CD3-zeta expression and numbers of CD4(+)/CD25(+)/FoxP3(+) regulatory T cells, CD15(+)/CD11b(+)/CD14(-) immature myeloid-derived cells, and CD8(+)gp100 tetramer-positive cells in the blood did not correlate with clinical benefit.
The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.
高剂量白细胞介素-2（IL-2）可使15%至20%的晚期黑色素瘤患者产生反应；5%至8%为持久完全缓解（CR）。HLA-A2限制性修饰的gp100肽（210M）可在体内诱导T细胞免疫，但其抗肿瘤活性较小，但据报道与高剂量IL-2联合使用时，有效率（RR）为42%（31例患者中有13例）。我们评估了210M与三种不同IL-2给药方案之一联合使用的效果，以确定是否有开展III期试验的依据。
在三项独立的II期试验中，黑色素瘤患者在第1、4、7和10周皮下注射210M，并在第1和3周（试验1）、第7和9周（试验2）或第1、4、7和10周（试验3）接受标准高剂量IL-2治疗。对治疗前后采集的外周血单个核细胞进行免疫分析。
1998年至2003年，纳入了131例HLA-A2阳性患者。中位随访时间为60个月，121例可评估患者的总体RR为16.5%（95%CI，10%至26%）；试验1（42例患者）的RR为23.8%，试验2（40例患者）为12.5%，试验3（39例患者）为12.8%。有11例CR（9%）和9例部分缓解（7%），11例患者（9%）在≥30个月时无疾病进展。包括CD3-ζ表达检测以及血液中CD4(+)/CD25(+)/FoxP3(+)调节性T细胞、CD15(+)/CD11b(+)/CD14(-)未成熟髓样来源细胞和CD8(+)gp100四聚体阳性细胞数量检测在内的免疫研究与临床获益无相关性。
结果再次证明高剂量IL-2对晚期黑色素瘤有效，但在三项II期试验中的任何一项中均未显示出疫苗与高剂量IL-2联合使用时所报道的有前景的临床活性。
