Cancer Cell:序贯组合疗法可以使治疗对侵袭性癌症患者更有效!

2021-08-20 Sunny MedSci原创

可抑制扩散,延长生存期!

由加州大学洛杉矶分校琼森综合癌症中心的研究人员领导的一项新的临床前研究表明,用免疫检查点抑制剂治疗患有侵袭性癌症的人,包括黑色素瘤、胰腺癌结直肠癌,然后迅速进行突变靶向治疗,可以帮助克服治疗抵抗并延长生存期。

免疫检查点抑制剂通过重新激活杀死肿瘤的免疫细胞或 T 细胞来发挥作用,而突变靶向疗法则可以杀死携带开启癌症驱动途径的特定突变的肿瘤,彻底改变了晚期癌症患者的治疗方式。然而,对每种疗法的耐药性是一个常见问题,尤其是当大脑中出现耐药性时,限制了这些新疗法的有效性。

最近的研究表明,将靶向 PD-1/L1 的免疫检查点抑制剂与 MAPK 靶向疗法(通常单独用于治疗癌症患者)相结合可能有助于克服治疗耐药性。然而,在他们的新工作中,加州大学洛杉矶分校的一个团队发现,简单地同时开始治疗并不是最佳选择。相反,从两剂抗 PD-1/L1 起始治疗,然后加入 MAPK 靶向治疗,在延长肿瘤缩小和防止耐药性发展方面更有效。

我们已经拥有强大的药物来对抗晚期癌症,知道如何合理地剂量、排序和组合它们为医生提供了以提高患者的生存率的机会。

在这项发表在Cancer Cell上的研究中,研究人员在人类黑色素瘤、胰腺癌和结直肠癌的多种动物模型中测试了不同的顺序组合方案,这些模型由BRAF、  NF1、  NRAS和 KRAS等基因的常见突变驱动 。

图形摘要

他们一致发现,只有一种方案的表现远远优于其他方案,并揭示了分子和细胞机制来解释为什么在组合之上进行测序可以最大限度地提高治疗效果。他们还分析了自己的临床试验数据,发现无意接受免疫检查点治疗的患者与未接受免疫检查点治疗的患者相比,随后对 MAPK 靶向治疗的反应更好。

研究团队表示,最佳方案导致肿瘤中‘好巨噬细胞’的最高水平以及负责杀死肿瘤的 T 细胞的克隆扩增。临床数据的回顾性分析支持他们的发现,但需要在根据该项动物研究专门设计的临床试验中前瞻性地测试提出的快速方案。

该团队还证明,在添加 MAPK 抑制剂之前,抗 PD-1/L1 治疗的合理排序可抑制黑色素瘤脑转移并提高小鼠的存活率。

研究人员在癌症扩散到的所有身体部位(包括大脑)中检测到强大的 T 细胞克隆扩增。研究小组发现,引入两种免疫检查点疗法:抗 PD-1/L1 和抗 CTLA-4,进一步消除了癌症扩散,包括扩散到大脑并延长小鼠的生存期。

在顺序组合方案中,该团队能够使身体的抗癌 T 细胞更容易看到肿瘤,并使 T 细胞的环境更适合它们的生长和肿瘤杀伤活性。

特别是在黑色素瘤中,研究人员对这种方案抑制治疗耐药性的效果感到惊讶,在大多数患有转移性黑色素瘤的动物在几周内死于脑转移的转移模型中,他们提出的方案提供了具有完全反应的生存期,通常可延长至 10 个月,这是目前最长的随访时间。

基于这些实验室发现,该团队已开始 在加州大学洛杉矶分校的临床试验中测试合理测序 。

参考资料:

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.DOI:10.1016/j.ccell.2021.07.023

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    2022-05-05 维他命
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    2021-08-22 sunyl07