荷兰癌症研究所Marleen Kok课题组近日取得一项新成果。他们提出了免疫诱导策略增强转移性三阴性乳腺癌对PD-1阻断的敏感性的强化试验。该成果于2019年6月发表在国际学术期刊《Nature Medicine》上。

在这项适应性、非比较性第2阶段试验的第一阶段，67名转移性三阴乳腺癌患者被随机分为多组方案联合治疗：（1）未诱导组，或2周低剂量诱导组，（2）放疗(38Gy)组，（3）环磷酰胺组，（4）顺铂组和（5）阿霉素组，所有患者均随后使用单抗体。在整个队列中，有治疗的客观反应率(ORR;iRECIST)为20%。其中大多数反应发生在顺铂组(ORR 23%)和阿霉素组(ORR 35%)。在阿霉素和顺铂的低剂量诱导后，作者检测到参与PD-1PD-L1(程序性死亡配体1)和T细胞细胞毒性通路的免疫相关基因上调。阿霉素诱导后炎症相关基因JAKSTAT和肿瘤坏死因子信号上调进一步支持了作者的结论。总体而言，本研究的临床和转化数据表明，短期的阿霉素和顺铂的诱导更有利的肿瘤微环境，增强了三阴乳腺癌对PD-1阻断的反应性。这些数据不仅在三阴乳腺癌得到了证实，同时也为PD1阻断抗体在其他类型癌症治疗前的临床预处理的探索提供了依据。

据悉，程序性细胞死亡蛋白1 (PD-1)阻断对转移性三阴性乳腺癌(TNBC)的疗效较低，这突显了使肿瘤微环境对PD-1阻断更敏感的策略的必要性。临床前研究表明，化疗和放疗具有免疫调节作用。

附：英文原文

Title: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial

Author: Leonie Voorwerk, Maarten Slagter, Hugo M. Horlings, Karolina Sikorska, Koen K. van de Vijver, Michiel de Maaker, Iris Nederlof, Roelof J. C. Kluin, Sarah Warren, SuFey Ong, Terry G. Wiersma, Nicola S. Russell, Ferry Lalezari, Philip C. Schouten, Noor A. M. Bakker, Steven L. C. Ketelaars, Dennis Peters, Charlotte A. H. Lange, Erik van Werkhoven, Harm van Tinteren, Ingrid A. M. Mandjes, Inge Kemper, Suzanne Onderwater, Myriam Chalabi, Sofie Wilgenhof, John B. A. G. Haanen, Roberto Salgado, Karin E. de Visser, Gabe S. Sonke, Lodewyk F. A. Wessels, Sabine C. Linn, Ton N. Schumacher, Christian U. Blank, Marleen Kok

Issue&Volume: Volume 25 Issue 6，June 2019

Abstract: The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (38Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAKSTAT and TNF- signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

DOI: 10.1038/s41591-019-0432-4

Source:https://www.nature.com/articles/s41591-019-0432-4