Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.
Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.
复制标题
用ipilimumab的tilsotolimod驱动抗PD-1难治性黑色素瘤中的肿瘤反应。
DOI：
10.1158/2159-8290.cd-20-1546
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发表时间：
2021-08
期刊：
影响因子：
28.2
通讯作者：
Diab A
中科院分区：
文献类型：
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作者：
Haymaker C;Johnson DH;Murthy R;Bentebibel SE;Uemura MI;Hudgens CW;Safa H;James M;Andtbacka RHI;Johnson DB;Shaheen M;Davies MA;Rahimian S;Chunduru SK;Milton DR;Tetzlaff MT;Overwijk WW;Hwu P;Gabrail N;Agrawal S;Doolittle G;Puzanov I;Markowitz J;Bernatchez C;Diab A
许多晚期黑色素瘤患者对免疫检查点抑制具有抗性。在ILLUMINATE-204 I/II期试验中，我们评估了抗PD-1耐药晚期黑色素瘤患者的肿瘤内替索莫德（一种研究性Toll样受体9激动剂）与全身性伊匹单抗。在所有患者中，48.4%发生了3/4级治疗后出现的不良事件。在推荐的II期剂量8 mg时，总体缓解率为22.4%，另有49%的患者病情稳定。观察了非注射病灶和预期对易普利姆玛单药治疗耐药的患者的反应。局部IFNα基因签名的快速诱导、树突状细胞成熟和抗原呈递的增强标志物以及T细胞克隆扩增与临床应答相关。该联合用药的III期临床试验（NCT 03445533）正在进行中。尽管最近在先进的黑色素瘤治疗的发展，大多数患者没有经历持久的反应。肿瘤内替索莫德注射激发快速的局部1型IFN应答，并且与伊匹单抗组合激活T细胞以促进临床活性，包括在远处病变和预期不对单独伊匹单抗应答的患者中。
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. 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.