小柯机器人

美国加州大学洛杉矶分校Roger S. Lo等研究人员合作发现，在MAPK抑制剂前使用抗PD-1/L1治疗可最大限度地提高抗肿瘤免疫力和疗效。

 

由于MAPK抑制剂（MAPKi）的临床获益增加与之前的免疫检查点治疗有关，研究人员在Braf^V600、Nras或Nf1突变驱动的黑色素瘤以及Kras^G12C驱动的结直肠癌和胰腺癌的皮下小鼠模型中比较了顺序和/或组合疗法的功效。MAPKi前先使用抗PD-1/L1可通过促进巨噬细胞的促炎症极化和干扰素-γ^hi的克隆扩张，以及高度表达激活基因的CD8⁺细胞毒性和增殖性（相对于CD4⁺调节性）T细胞来优化反应的持久性。

由于黑色素瘤脑转移（MBM）的治疗抗性限制了患者的生存，研究人员证明在MAPKi联合治疗前进行抗PD-1/L1治疗可抑制MBM并提高小鼠生存率，并在颅内和颅外转移部位都有强大的T细胞克隆扩展。研究人员建议，在MAPKi联合治疗前进行简短的抗PD-1/L1（±抗CTLA-4）用药的临床测试，从而抑制治疗性抵抗。

 

据介绍，合理安排PD-1/L1和MAPK靶向疗法的顺序和组合，可能会克服先天和后天的抗性。

 

附：英文原文

Title: Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Author: Yujue Wang,Sixue Liu,Zhentao Yang,Marco Piva,Gatien Moriceau

Issue&Volume: 2021/08/19

Abstract: Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

DOI: https://doi.org/10.1016/j.ccell.2021.07.023

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00402-5#