【原】三阴性乳腺癌治疗磨刀不误砍柴工

　　通过免疫检查点抑制剂阻断程序性细胞死亡蛋白1（PD-1）对于早期三阴性乳腺癌的疗效较好，不过对于晚期三阴性乳腺癌的疗效较差，故有必要研究促使肿瘤免疫微环境对PD-1阻断剂更敏感的新策略。既往临床前研究结果表明，免疫治疗前的化疗和放疗对于肿瘤免疫微环境具有调节作用，被称为免疫诱导。

　　2019年5月13日，英国《自然》旗下《自然医学》在线发表荷兰癌症研究所、乌得勒支肿瘤基因研究所、根特大学医院、美国西雅图纳米基因科技、比利时安特卫普医院、澳大利亚墨尔本大学彼得麦卡伦癌症中心的TONIC研究报告，探讨了增强转移性三阴性乳腺癌对PD-1阻断剂尼沃鲁单抗敏感性的免疫诱导策略。

TONIC: Nivolumab After Induction Treatment in Triple-negative Breast Cancer Patients (NCT02499367)

　　该适应性随机化II期研究第一阶段将66例转移性三阴性乳腺癌患者随机分为5组：

• 无诱导组：观察2周→尼沃鲁单抗每2周3mg/kg（12例）

• 放疗诱导组：放疗2周每次8Gy×3次→尼沃鲁单抗每2周3mg/kg（12例）

• 环磷酰胺诱导组：环磷酰胺每天50mg口服×2周→尼沃鲁单抗每2周3mg/kg（12例）

• 顺铂诱导组：顺铂每周40mg/m²静脉注射×2周→尼沃鲁单抗每2周3mg/kg（13例）

• 多柔比星诱导组：多柔比星（阿霉素）每周15mg静脉注射×2周→尼沃鲁单抗每2周3mg/kg（17例）

　　结果，根据免疫治疗实体肿瘤缓解评估标准（iRECIST）比较各组客观缓解率：

• 全部患者：20%

• 无诱导组：17%

• 放疗诱导组：8%

• 环磷酰胺诱导组：8%

• 顺铂诱导组：23%

• 多柔比星诱导组：35%

　　多柔比星、顺铂诱导后，PD-1、程序性细胞死亡配体1（PD-L1）、T淋巴细胞毒性通路的免疫相关基因表达上调。多柔比星诱导后，炎症、JAK激酶→信号转导及转录激活蛋白（STAT）、肿瘤坏死因子-α（TNF-α）信号传导相关基因表达上调。

　　因此，该研究的临床和转化数据表明，短期多柔比星和顺铂化疗可以诱导更有利的肿瘤微环境，并且增加三阴性乳腺癌对PD-1阻断剂的客观缓解率，故有必要对三阴性乳腺癌进一步确认这些数据，并对其他癌症进一步探索免疫治疗前的诱导治疗。

Nat Med. 2019 May 13. [Epub ahead of print]

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

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.

The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Ghent University Hospital, Ghent, Belgium; NanoString Technologies, Inc., Seattle, WA, USA; GZA-ZNA Ziekenhuizen, Antwerp, Belgium; Peter Mac Callum Cancer Center, Melbourne, Victoria, Australia.

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 (3×8 Gy), (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-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α 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