Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma.
Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma.
复制标题
在转移性黑色素瘤患者中，用CpG-A Toll样受体9激动剂Vidutolimod克服PD-1阻滞性。
DOI：
10.1158/2159-8290.cd-21-0425
复制
发表时间：
2021-12-01
期刊：
影响因子：
28.2
通讯作者：
Milhem MM
中科院分区：
文献类型：
--
作者：
Ribas A;Medina T;Kirkwood JM;Zakharia Y;Gonzalez R;Davar D;Chmielowski B;Campbell KM;Bao R;Kelley H;Morris A;Mauro D;Wooldridge JE;Luke JJ;Weiner GJ;Krieg AM;Milhem MM
肿瘤内vidutolimod（CpG-A TLR 9激动剂）与pembrolizumab一起在I期试验中克服了25%的转移性黑色素瘤患者的PD-1阻断抗性，毒性可控。对PD-1阻断治疗耐药的晚期黑色素瘤患者的治疗选择有限。Vidutolimod（以前称为CMP-001）是一种含有CpG-A Toll样受体9（TLR 9）激动剂的病毒样颗粒，可通过触发强烈的IFN应答来诱导和吸引抗肿瘤T细胞，从而逆转PD-1阻断抗性。在这项Ib期研究的剂量递增部分中，将vidutolimod以递增剂量与静脉内pembrolizumab一起瘤内给药至44名患有晚期黑色素瘤的患者，这些患者在既往抗PD-1治疗中患有疾病进展或疾病稳定。vidutolimod和pembrolizumab的组合具有可管理的安全性特征，并且在25%的患者中观察到持久的反应，在注射和非注射病变中肿瘤消退，包括内脏病变。对vidutolimod和pembrolizumab有反应的患者在基线时肿瘤无炎症，治疗后IFNγ基因签名诱导，以及IFN诱导型趋化因子CXCL 10的全身表达增加。在晚期黑色素瘤患者中进行的这项Ib期研究中，肿瘤内TLR 9激动剂vidutolimod与pembrolizumab的组合具有可管理的安全性特征，并显示出有希望的临床活性，支持vidutolimod的进一步临床开发，以通过诱导IFN应答来克服PD-1阻断抗性。 参见Sullivan的相关评论，第2960页。 这篇文章在本期专题中突出显示，第2945页
Intratumoral vidutolimod (CpG-A TLR9 agonist) together with pembrolizumab overcomes PD-1 blockade resistance in 25% of patients with metastatic melanoma with manageable toxicities in a phase I trial. Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10. In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response. See related commentary by Sullivan, p. 2960. This article is highlighted in the In This Issue feature, p. 2945