Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients
Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients
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DOI：
10.1158/1078-0432.ccr-07-4711
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发表时间：
2008-07-15
影响因子：
11.5
通讯作者：
de Gruijl, Tanja D.
中科院分区：
文献类型：
--
作者：
Molenkamp, Barbara G.;Sluijter, Berbel J. R.;de Gruijl, Tanja D.
目的：黑色素瘤前哨淋巴结（SLN）免疫效应功能受损可能导致早期转移。PF-3512676（以前称为CpG 7909）的局部给药显示了对黑色素瘤SLN中树突状细胞和T细胞亚群的免疫刺激作用。在这里，我们着手确定这些PF-3512676诱导的免疫刺激作用是否转化为更高频率的黑色素瘤特异性CD 8（+）T cells.Experimental Design：24例I至III期黑色素瘤患者随机接受术前局部给药PF-3512676或生理盐水。采用IFN-γ ELISPOT法检测21例患者SLN和外周血中CD 8（+）T细胞对多种黑色素瘤相关抗原（MAA）衍生的HLA-A1/A2/A3限制性表位的反应性。结果：盐水组SLN中针对>1个MAA表位的黑色素瘤特异性CD 8（+）T细胞应答率为0/11，PF-3512676组为5/10（P = 0.012）。在这5名应答患者中，4名还对血液中的>1个MAA表位具有可测量的应答。SLN中MAA特异性CD 8（+）T细胞和NK细胞的频率增加与CpG诱导的浆细胞样树突状细胞成熟相关。这些数据显示PF-3512676单次给药后黑色素瘤特异性CD 8（+）T细胞频率增加以及效应NK细胞率增加，因此支持局部PF-3512676的效用。3512676作为早期黑素瘤的辅助治疗给药，以尝试阻止转移性扩散。
Purpose: Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. Local administration of PF-3512676 (formerly known as CpG 7909) has shown immunostimulatory effects of both dendritic cell and T-cell subsets in the melanoma SLN. Here, we set out to ascertain whether these PF-3512676-induced immunostimulatory effects translate into higher frequencies of melanoma-specific CD8(+) T cells.Experimental Design: Twenty-four stage I to III melanoma patients were randomized to preoperative local administration of either PF-3512676 or saline. CD8(+) T cells from SLN and peripheral blood were tested for reactivity by IFN-gamma ELISPOT assay against several HLA-A1/A2/A3-restricted epitopes derived from various melanoma-associated antigens (MAA) in 21 of 24 enrolled patients. Frequencies of natural killer (NK) cells and frequencies and maturation state of dendritic cell subsets in the SLN were determined by flow cytometry.Results: Melanoma-specific CD8(+) T-cell response rates against >1 MAA epitope in the SLN were 0 of 11 for the saline group versus 5 of 10 for the PF-3512676-administered group (P = 0.012). Of these 5 responding patients, 4 also had a measurable response to >1 MAA epitope in the blood. Increased frequencies in the SLN of both MAA-specific CD8(+) T cells and NK cells correlated to CpG-induced plasmacytoid dendritic cell maturation.Conclusions: These data show an increase in melanoma-specific CD8(+) T-cell frequencies as well as an increased effector NK cell rate after a single dose of PF-3512676 and thus support the utility of local PF-3512676 administration as adjuvant treatment in early-stage melanoma to try and halt metastatic spread.