Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2021 Aug;11(8):1996-2013. doi: 10.1158/2159-8290.CD-20-1546. Epub 2021 Mar 11.
Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone..
许多晚期黑色素瘤患者对免疫检查点抑制剂有耐药性。在 ILLUMINATE-204 期 I/II 试验中，我们评估了局部注射替西莫单抗（一种研究性 Toll 样受体 9 激动剂）联合系统应用伊匹单抗在抗 PD-1 耐药的晚期黑色素瘤患者中的疗效。所有患者中，有 48.4%经历了 3/4 级治疗相关不良事件。在推荐的 8mg 二期剂量下，总缓解率为 22.4%，另有 49%的患者疾病稳定。在非注射病灶和预计对伊匹单抗单药治疗耐药的患者中观察到了应答。快速诱导局部 IFNα 基因特征、树突状细胞成熟和增强的抗原呈递标志物以及 T 细胞克隆扩增与临床应答相关。一项该联合用药的三期临床试验（NCT03445533）正在进行中。意义：尽管晚期黑色素瘤治疗最近取得了进展，但大多数患者并未获得持久缓解。局部注射替西莫单抗可引发快速的局部 1 型 IFN 反应，与伊匹单抗联合使用可激活 T 细胞以促进临床活性，包括在远处病灶和预计对伊匹单抗单药治疗无应答的患者中。
