Siu Lillian L, Postel-Vinay Sophie, Villanueva-Vázquez Rafael, de Velasco Guillermo, Castanon Alvarez Eduardo, Kyriakopoulos Christos E, Johnson Melissa, Ouali Kaïssa, McMorn Stephen, Angell Helen K, Ng Felicia, Saran Shashank, Bayat Mahdiye, Collins Teresa, Roy Archana, Lambert Arthur W, Cho Song, Miller Neil, Petruzzelli Michele, Stone John, Massard Christophe
Princess Margaret Cancer Centre, Toronto, Canada.
Institut Gustave Roussy, Villejuif, France.
Clin Cancer Res. 2025 Apr 14;31(8):1449-1462. doi: 10.1158/1078-0432.CCR-24-1818.
AZD8701 uses next-generation antisense oligonucleotide (ASO) technology to selectively reduce human forkhead box P3 (FOXP3) expression in regulatory T cells, reversing their immunosuppressive function. FOXP3 ASO alone or with PD-(L)1 inhibition attenuated tumor growth in mice. We report a phase I study of AZD8701 alone or combined with durvalumab in patients with advanced solid tumors.
Eligible patients had solid tumors and received prior standard-of-care treatment, including anti-PD-(L)1 therapy. Patient cohorts were treated with AZD8701 intravenously weekly at escalating doses, either alone (60-960 mg) or combined (240-720 mg) with durvalumab 1,500 mg intravenous every 4 weeks. The primary objective was safety and tolerability, with the aim of determining the MTD.
Forty-five patients received AZD8701 monotherapy, and 18 received AZD8701 with durvalumab. One dose-limiting toxicity (increased alanine aminotransferase) occurred with AZD8701 960 mg. The most common adverse events related to AZD8701 monotherapy were fatigue (22.2%), asthenia, pyrexia, and increased alanine aminotransferase (20% each); the safety profile was similar when combined with durvalumab. With AZD8701 monotherapy, 24.4% and 15.6% of the patients had stable disease for ≥16 and ≥24 weeks, respectively; one patient treated with AZD8701 720 mg and durvalumab had a partial response. FOXP3 mRNA changes were heterogeneous (8/13 patients showed a reduction), with no clear dose relationship. ASO accumulated in the tumor epithelium and stroma.
This study demonstrates the clinical feasibility of ASO therapy, with generally manageable adverse events, FOXP3 knockdown, and ASO delivery to the tumor.
AZD8701采用下一代反义寡核苷酸（ASO）技术，选择性降低调节性T细胞中人叉头框蛋白P3（FOXP3）的表达，逆转其免疫抑制功能。单独使用FOXP3 ASO或联合PD-（L）1抑制可减缓小鼠肿瘤生长。我们报告了一项关于AZD8701单独或联合度伐利尤单抗治疗晚期实体瘤患者的I期研究。
符合条件的患者患有实体瘤，并接受过包括抗PD-（L）1治疗在内的先前标准治疗。患者队列接受每周一次静脉注射递增剂量的AZD8701治疗，剂量为单独使用（60-960毫克）或联合使用（240-720毫克）度伐利尤单抗，度伐利尤单抗每4周静脉注射1500毫克。主要目标是安全性和耐受性，目的是确定最大耐受剂量（MTD）。
45例患者接受了AZD8701单药治疗，18例患者接受了AZD8701联合度伐利尤单抗治疗。960毫克AZD8701出现了1例剂量限制性毒性（丙氨酸转氨酶升高）。与AZD8701单药治疗相关的最常见不良事件为疲劳（22.2%）、乏力、发热和丙氨酸转氨酶升高（均为20%）；与度伐利尤单抗联合使用时的安全性概况相似。接受AZD8701单药治疗的患者中，分别有24.4%和15.6%的患者疾病稳定≥16周和≥24周；1例接受720毫克AZD8701联合度伐利尤单抗治疗的患者出现部分缓解。FOXP3 mRNA变化具有异质性（13例患者中有8例显示降低），无明确的剂量关系。ASO在肿瘤上皮和基质中蓄积。
本研究证明了ASO疗法的临床可行性，其不良事件总体可控，可实现FOXP3基因敲低并将ASO递送至肿瘤部位。
