Comin-Anduix Begoña, Lee Yohan, Jalil Jason, Algazi Alain, de la Rocha Pilar, Camacho Luis H, Bozon Viviana A, Bulanhagui Cecile A, Seja Elisabeth, Villanueva Arturo, Straatsma Bradley R, Gualberto Antonio, Economou James S, Glaspy John A, Gomez-Navarro Jesus, Ribas Antoni
Department of Surgery, Division of Surgical Oncology, University of California Los Angeles, Los Angeles, CA, USA.
J Transl Med. 2008 May 1;6:22. doi: 10.1186/1479-5876-6-22.
CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.
Peripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4+/CD8+ cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis.
Three of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8+ cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup.
Administration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood.
NCT00086489.
CTLA4阻断抗体可使部分黑色素瘤患者的肿瘤消退。对外周血免疫参数的分析可能有助于明确反应的介导方式。
对10mg/kg每月接受曲美木单抗（原CP-675,206）治疗的HLA-A*0201阳性晚期黑色素瘤患者，在最初4个周期内反复采集外周血样本。样本通过以下方法进行分析：1）四聚体和ELISPOT检测对巨细胞病毒、EB病毒、MART1、gp100和酪氨酸酶的反应性；2）CD4+/CD8+细胞上活化的HLA-DR和记忆性CD45RO标志物；3）优先由调节性T细胞表达的FoxP3转录因子的mRNA实时定量PCR。主要终点是通过四聚体检测MART1特异性T细胞的差异。使用聚类分析探索免疫数据的显著趋势。
12名符合免疫监测条件的患者中有3名出现持续>2年无复发的肿瘤消退。通过四聚体检测，MART1特异性T细胞百分比无显著变化。此外，其他抗原特异性CD8+细胞群体、FoxP3转录本或T细胞活化或记忆标志物表面表达的总体变化在给药后无普遍趋势。基于免疫监测数据的无监督层次聚类随机分离患者。然而，根据T细胞活化或记忆标志物进行聚类，将有临床反应的患者和大多数有炎症毒性的患者分为一个共同亚组。
对晚期黑色素瘤患者给予CTLA4阻断抗体曲美木单抗可使部分患者产生长期肿瘤反应。T细胞活化和记忆标志物是该抗体在外周血中药效学作用的唯一读数。
NCT00086489。
