几种临床试验表明,与单独的抗PD-(L)1抑制剂相比,组合抗CTLA-4抑制剂和抗PD-(L)1抑制剂增加了总反应。靶向PD-1和CTLA-4的双特异性抗体可以是阻断CTLA-4和PD-1的新方法。

Until now, 2 types of immune checkpoint inhibitors have shown clinical effectivity against a broad range of tumors: anti-CTLA-4 inhibitors (e.g. ipilimumab and tremelimumab) and PD-(L)1 inhibitors (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab). There is a rationale to combine these types of immune checkpoint inhibitors because anti-CTLA-4 inhibitors increase the expression of PD-L1 in some tumors and the combination of anti-CTLA-4 inhibition and PD-(L)1 inhibition favors effector T cell recruitment in preclinical tumor models [1]. In addition, several clinical trials have shown that combining an anti-CTLA-4 inhibitor and an anti-PD-(L)1 inhibitor increases the overall response compared with an anti-PD-(L)1 inhibitor alone [2]. However, the combination also induces more serious adverse events (grade ≥3).

MGD019和AK104都是针对CTLA-4和PD-1的双特异性四价抗体。这使得这些分子成为同时阻断CTLA-4和PD-L1的潜在新候选分子,从而模拟了nivolumab + ipilimumab双重免疫检查点封锁的临床效果。Manish Sharma教授(START Midwest, Grand Rapids, USA)介绍了MGD019在晚期实体瘤[3]患者中的第一阶段,开放标签,剂量递增研究的结果。在数据截止时,33例患者(39%的检查点经历,3个中位既往治疗线)的治疗剂量从0.03 mg/kg增加到10 mg/kg。未定义最大耐受剂量。33例患者中有26例(78.8%)发生了治疗相关不良事件,最常见的是疲劳(24%)、恶心、关节痛、瘙痒和皮疹(各18%)。≥3级的治疗相关不良事件发生率为24.2%。免疫相关的严重不良事件包括肠炎、小肠结肠炎、肺炎和心肌炎(各1例)。MGD019的半衰期为12天;每3周剂量≥3.0 mg时,观察到与循环T细胞完全靶向结合。 Among 25 response-evaluable patients, 4 objective responses were observed also in tumor types that are typically not responsive to checkpoint blockade (microsatellite-stable colorectal cancer, metastatic thymoma [both confirmed partial response], anti-PD-L1-refractory serous fallopian tube carcinoma [unconfirmed partial response with >50% reduction of CA-125], and prostatic adenocarcinoma [confirmed complete response with resolution of PSA]); 9 patients had stable disease. Dose-dependent ICOS upregulation on circulating CD4-positive T cells was evident, consistent with CTLA-4 engagement. A phase 2 monotherapy in select expansion cohorts is forthcoming.

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此外,Michael Milward教授(西澳大利亚大学,澳大利亚)介绍了在18例间皮瘤患者中使用AK104进行的1期临床试验的结果。18例患者中有3例(16.7%)出现3-4级治疗相关不良事件(发热、1型糖尿病和输液相关反应);另外9名受试者经历了1-2级治疗相关的不良事件。最常见的治疗相关不良事件是皮疹(6例)和输液相关反应(5例)。有15例患者的肿瘤评估资料。确诊客观缓解率为20%,疾病控制率为80%。中位无进展生存期(PFS)为5.6个月;AK104剂量≥4 mg/kg (n=16)的患者中位无生存期为12.9个月。

总之,这两项研究的初始结果表明AK104以及MGD019具有良好的耐受性,并且具有令人振奋的抗肿瘤活性,这使得它们成为潜在的新治疗选择。

  1. shi lz等。T细胞中的相互依赖的IL-7和IFN-γ信号传导通过组合α-CTLA-4 +α-PD-1治疗来控制肿瘤根除。NAT Communce。2016;7:12335。
  2. Nivolumab和Nivolumab联合Ipilimumab治疗晚期癌症的疗效和安全性比较:系统回顾和荟萃分析。杂志。2020;11: 40
  3. Sharma M,等。MGD019是一种实验性双特异性PD-1 x CTLA-4 DART®分子,用于晚期实体肿瘤患者。ESMO 2020虚拟会议,摘要1020O。
  4. Millward M等。针对PD-1和CTLA-4的双特异性抗体AK104在复发或标准治疗难治的间皮瘤患者中的安全性和抗肿瘤活性。ESMO 2020虚拟会议,摘要1021O