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都是双特异性的四价抗体,靶向CTLA-4和PD-1。这使得这些分子潜在的新候选者同时阻止CTLA-4和PD-L1,因此模拟了双免疫检查点封闭的临床效果。Nivolumab加Ipilimumab。Manish Sharma教授(开始中西部,大急流,美国)呈现了先进实体肿瘤患者的第1阶段,第一款,开放式,剂量升级的结果[3]。在数据截止,33名患者(39%的检查点经验丰富的3个中位数的治疗中)以0.03至10mg / kg的剂量升级处理。没有定义最大耐受剂量。治疗相关的不良事件发生在33例(78.8%)患者中,最常见的疲劳(24%),恶心,关节痛,瘙痒和皮疹(每项18%)。≥3种治疗相关不良事件的速率为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(每次n = 1)。MGD019的半衰期为12天; full on-target binding to circulating T cells was observed at doses ≥3.0 mg every 3 weeks. 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,迈克尔·米兰(澳大利亚大学)迈克尔·米兰教授由18名间皮瘤患者中AK104的临床第1次试验结果提出了结果。18名患者中的三个(16.7%)具有3-4级与治疗相关的不良事件(发烧,1型糖尿病和输液相关的反应);另外9名受试者经历了1-2级与治疗相关的不良事件。最常见的治疗相关的不良事件是皮疹(6名患者)和与输液相关的反应(5名患者)。肿瘤评估数据可用于15名患者。确认的客观反应率为20%,疾病控制率为80%。中位进展的生存(PFS)为5.6个月;在4mg / kg或更多(n = 16)的剂量中接受Ak104的患者中位数PFS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. 杨y,e al。Nivolumab和Nivolumab Plus IpiLimumab在晚期癌症中的比较疗效和安全性:系统审查和荟萃分析。前药狼。2020;11:40
  3. Sharma M,等MGD019的I阶段I,第一型,开放标签,剂量升级研究,一种晚期实体瘤患者的研究双特异性PD-1 X CTLA-4DART®分子。ESMO 2020虚拟会议,摘要1020O。
  4. Millward M等人。Ak104的安全性和抗肿瘤活性,靶向靶向PD-1和CTLA-4的双特异性抗体,所述间皮瘤患者对标准疗法复发或难治。ESMO 2020虚拟会议,摘要1021O