Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA.
J Clin Immunol. 2011 Aug;31(4):690-8. doi: 10.1007/s10875-011-9530-x. Epub 2011 Apr 13.
Cycloxygenase-2 (COX-2) is an enzyme involved in prostaglandin E2 (PGE(2)) synthesis associated with higher renal cell carcinoma stage. COX-2 inhibition enhances interferon (IFN-α) anti-tumor immune effects in pre-clinical models. A phase II trial of celecoxib and IFN-α in a targeted population of metastatic renal cell carcinoma patients with maximal COX-2 expression was conducted.
Cytokine-naive metastatic renal cell carcinoma patients with tumors expressing ≥10% maximal COX-2 staining by immunohistochemistry received IFN-α 5 million units daily and celecoxib 400 mg orally twice daily in an open-label, single-arm phase II trial.
There were 3 partial responses among 17 patients (objective response rate 18%; 95% confidence interval, 4-43%). Time to progression was 5.6 months. Increased tumor staining 3+ for COX-2 was associated with increased baseline peripheral blood PGE(2) levels, and these patients demonstrated less PGE(2) decrease with therapy. Patients with more 3+ COX-2 staining had significantly more CD3(+) (p = 0.004) and CD4(+) (p = 0.002) IFN-γ T cells at baseline and a significantly greater decrease in these cells with therapy.
Celecoxib plus IFN-α in renal cell carcinoma (RCC) patients with maximally staining COX-2 tumors does not significantly enhance overall response rates over IFN monotherapy.
COX-2-expressing RCC demonstrates inherent immunosuppression. COX-2 inhibition with IFN results in minimal immunomodulation and no augmented clinical activity in RCC.
环氧化酶-2（COX-2）是一种与前列腺素 E2（PGE2）合成相关的酶，与肾细胞癌的较高分期有关。COX-2 抑制作用可增强临床前模型中干扰素（IFN-α）的抗肿瘤免疫效应。在 COX-2 表达最高的转移性肾细胞癌患者的目标人群中进行了塞来昔布和 IFN-α的 II 期试验。
采用免疫组织化学法检测肿瘤 COX-2 表达≥10%的细胞因子初治转移性肾细胞癌患者接受 IFN-α 500 万单位/天，塞来昔布 400mg 口服，每日 2 次，开放性、单臂 II 期试验。
17 例患者中有 3 例部分缓解（客观缓解率 18%；95%置信区间，4-43%）。无进展时间为 5.6 个月。COX-2 染色 3+的肿瘤增加与基线外周血 PGE2 水平升高相关，这些患者的治疗后 PGE2 下降减少。COX-2 染色 3+更多的患者基线时 CD3+（p=0.004）和 CD4+（p=0.002）IFN-γ T 细胞更多，治疗后这些细胞的下降幅度显著更大。
在 COX-2 染色肿瘤最大的肾细胞癌（RCC）患者中，塞来昔布加 IFN-α并未显著提高总反应率，优于 IFN 单药治疗。
COX-2 表达的 RCC 表现出固有免疫抑制。IFN 引起的 COX-2 抑制导致最小的免疫调节作用，并且在 RCC 中没有增强的临床活性。
