Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.
Department of Clinical Research in Tumor Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Clin Cancer Res. 2015 Oct 1;21(19):4327-36. doi: 10.1158/1078-0432.CCR-15-0357.
FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients.
We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed.
The results showed that KW-0761 infusion in a dose range between 0.1 mg/kg and 1.0 mg/kg was safe and well tolerated. No dose-limiting toxicity was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients.
The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.
FoxP3(+)Treg 抑制针对肿瘤的免疫反应。KW-0761 是一种人源化抗人 CCR4 单克隆抗体 (mAb)，具有抗体依赖性细胞细胞毒性活性。通过 KW-0761 输注耗竭 CCR4 表达的 FoxP3(+)CD4 Treg ，在实体瘤患者中进行了研究。
我们对 7 例肺癌和 3 例食管癌患者进行了 KW-0761 输注的 I 期临床试验。分析了毒性、临床疗效、包括 Treg 在内的淋巴细胞亚群变化以及免疫反应的诱导。
结果表明，KW-0761 输注剂量在 0.1mg/kg 至 1.0mg/kg 之间是安全且耐受良好的。未观察到剂量限制性毒性。10 例患者中有 4 例在治疗期间出现稳定的疾病且为长期幸存者。在治疗过程中监测外周血单个核细胞中的 FoxP3(+)Treg 表明，即使使用最低剂量 0.1mg/kg，也能有效耗竭这些细胞。Th1 CD4 T 细胞和 CD8 T 细胞的减少是有限的，而 Th2 和 Th17 CD4 T 细胞则显著减少。一些患者观察到对癌症/睾丸 (CT) 抗原的免疫反应和对甲状腺过氧化物酶的自身抗体反应。
这些发现表明，KW-0761 输注后可耗竭 Treg 并可能发生免疫反应。与其他免疫疗法（如癌症疫苗或检查点抑制剂）联合使用 KW-0761 来耗竭 FoxP3(+)Treg 是增强免疫反应的一种有前途的方法。
