Authors' Affiliations: Roche Pharma Research and Early Development, Nutley, New Jersey; Roche Diagnostics GmbH, Pharma Research & Early Development, Nonnenwald, Penzberg, Germany; and Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland.
Clin Cancer Res. 2013 Oct 15;19(20):5686-98. doi: 10.1158/1078-0432.CCR-13-0405. Epub 2013 Aug 23.
To explore the role of TWEAK in tumor growth and antitumor immune response and the activity and mechanism of RG7212, an antagonistic anti-TWEAK antibody, in tumor models.
TWEAK-induced signaling and gene expression were explored in tumor cell lines and inhibition of these effects and antitumor efficacy with RG7212 treatment was assessed in human tumor xenograft-, patient-derived xenograft, and syngeneic tumor models and phase I patients. Genetic features correlated with antitumor activity were characterized.
In tumor cell lines, TWEAK induces proliferation, survival, and NF-κB signaling and gene expression that promote tumor growth and suppress antitumor immune responses. TWEAK-inducible CD274, CCL2, CXCL-10 and -11 modulate T-cell and monocyte recruitment, T-cell activation, and macrophage differentiation. These factors and TWEAK-induced signaling were decreased, and tumor, blood, and spleen immune cell composition was altered with RG7212 treatment in mice. RG7212 inhibits tumor growth in vivo in models with TWEAK receptor, Fn14, expression, and markers of pathway activation. In phase I testing, signs of tumor shrinkage and stable disease were observed without dose-limiting toxicity. In a patient with advanced, Fn14-positive, malignant melanoma with evidence of tumor regression, proliferation markers were dramatically reduced, tumor T-cell infiltration increased, and tumor macrophage content decreased. Antitumor activity, a lack of toxicity in humans and animals and no evidence of antagonism with standard of care or targeted agents in mice, suggests that RG7212 is a promising agent for use in combination therapies in patients with Fn14-positive tumors.
探索 TWEAK 在肿瘤生长和抗肿瘤免疫反应中的作用，以及拮抗型抗 TWEAK 抗体 RG7212 在肿瘤模型中的活性和机制。
在肿瘤细胞系中探索 TWEAK 诱导的信号转导和基因表达，评估 RG7212 对这些效应的抑制作用以及在人肿瘤异种移植、患者来源的异种移植和同基因肿瘤模型和 I 期患者中的抗肿瘤疗效。鉴定与抗肿瘤活性相关的遗传特征。
在肿瘤细胞系中，TWEAK 诱导增殖、存活和 NF-κB 信号转导和基因表达，促进肿瘤生长并抑制抗肿瘤免疫反应。TWEAK 诱导的 CD274、CCL2、CXCL-10 和 -11 调节 T 细胞和单核细胞募集、T 细胞激活和巨噬细胞分化。用 RG7212 处理小鼠后，这些因子和 TWEAK 诱导的信号转导减少，肿瘤、血液和脾脏免疫细胞组成发生改变。在 TWEAK 受体 Fn14 和途径激活标志物表达的模型中，RG7212 在体内抑制肿瘤生长。在 I 期测试中，观察到无剂量限制性毒性的肿瘤缩小和稳定疾病的迹象。在一名晚期、Fn14 阳性、恶性黑色素瘤患者中，有肿瘤消退的证据，增殖标志物显著降低，肿瘤 T 细胞浸润增加，肿瘤巨噬细胞含量减少。抗肿瘤活性、人类和动物无毒性以及在小鼠中与标准护理或靶向药物无拮抗作用的证据表明，RG7212 是 Fn14 阳性肿瘤联合治疗中很有前途的药物。
