Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer.
Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer.
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DOI：
10.1158/0008-5472.can-07-0199
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发表时间：
2007-08-01
期刊：
影响因子：
11.2
通讯作者：
Hayday AC
中科院分区：
文献类型：
--
作者：
Dieli F;Vermijlen D;Fulfaro F;Caccamo N;Meraviglia S;Cicero G;Roberts A;Buccheri S;D'Asaro M;Gebbia N;Salerno A;Eberl M;Hayday AC
越来越多的证据表明γδ T细胞具有强大的抗肿瘤活性，这表明它们在免疫治疗中的价值，特别是在转移性癌等未满足需求的领域。为此，我们在转移性前列腺癌中启动了一项I期临床试验，以检查单独使用γδ T细胞激动剂唑来膦酸盐或与低剂量白细胞介素2（IL-2）联合使用以激活外周血γδ细胞的可行性和后果。每组各有9名患者，两种治疗均未显示明显的毒性。大多数患者接受唑来膦酸+ IL-2治疗，但相反，只有2例接受唑来膦酸治疗的患者显示外周γδ细胞向激活的效应记忆样状态（TEM）的显著长期转变，产生IFN-γ和穿孔素。这些患者还维持肿瘤坏死因子相关凋亡诱导配体（TRAIL）的血清水平，这与显示TRAIL由通过T细胞受体和IL-2活化的γδ细胞产生的平行微阵列分析一致。此外，TEMγδ细胞的数量与前列腺特异性抗原水平下降和客观临床结果（包括3例部分缓解和5例疾病稳定）具有统计学显著相关性。相比之下，大多数仅用唑来膦酸盐治疗的患者未能维持γδ细胞数量或血清TRAIL，并显示进行性临床恶化。因此，唑来膦酸+ IL-2代表了一种新的、安全的和可行的方法，用于诱导转移性癌患者的免疫学和临床应答，可能为特定的给药方法提供了显著增加的窗口。此外，γδ细胞表型和可能的血清TRAIL可能构成转移性癌中唑来膦酸盐+ IL-2治疗后预后的新生物标志物。[Cancer Res 2007;67（15）：7450-7]
The increasing evidence that γδ T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the γδ T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood γδ cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral γδ cells toward an activated effector-memory–like state (TEM), producing IFN-γ and perforin. These patients also maintained serum levels of tumor necrosis factor–related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by γδ cells activated via the T-cell receptor and IL-2. Moreover, the numbers of TEMγδ cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either γδ cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, γδ cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma. [Cancer Res 2007;67(15):7450–7]