Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade
Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade
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DOI：
10.1126/scitranslmed.aac4925
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发表时间：
2015-11-25
影响因子：
17.1
通讯作者：
Zippelius, Alfred
中科院分区：
文献类型：
--
作者：
Mueller, Philipp;Kreuzaler, Matthias;Zippelius, Alfred
使用抗体药物偶联物（例如 HER2 导向的 ado-trastuzumab emtansine (T-DM1)）进行靶向药物递送已成为癌症治疗的强大策略。我们证明，T-DM1 在早期乳腺癌患者（WSG-ADAPT 试验）和表达 HER2 的原位肿瘤模型中特别有效地激发抗肿瘤免疫。在后者中，尽管对免疫疗法存在主要耐药性，但 T-DM1 和抗 CTLA-4/PD-1（细胞毒性 T 淋巴细胞相关蛋白 4/程序性细胞死亡蛋白 1）的联合治疗是有效的，因为它触发了先天性和适应性免疫。肿瘤排斥伴随着大量 T 细胞浸润、T(H)1（辅助 T 1）细胞极化，以及值得注意的是，调节性 T 细胞的大幅增加。调节性 T 细胞的耗竭会导致炎症和组织损伤，这意味着它们在治疗期间保护宿主方面发挥着重要作用。这项研究提供了对 T-DM1 治疗活性机制的见解以及免疫疗法潜在治疗组合策略的基本原理。
Targeted drug delivery with antibody-drug conjugates such as the HER2-directed ado-trastuzumab emtansine (T-DM1) has emerged as a powerful strategy for cancer therapy. We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumormodel. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity. Tumor rejection was accompanied bymassive T cell infiltration, T(H)1 (T helper 1) cell polarization, and, notably, a substantial increase in regulatory T cells. Depletion of regulatory T cells resulted in inflammation and tissue damage, implying their essential role in protecting the host during therapy. This study provides insights into the mechanisms of T-DM1' s therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.