Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Department of Medicine-Oncology, Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA.
Breast Cancer Res Treat. 2022 Jan;191(2):291-302. doi: 10.1007/s10549-021-06423-0. Epub 2021 Oct 30.
Breast cancer has historically been considered a non-immunogenic tumor. Multiple studies over the last 10-15 years have demonstrated that a small subset of breast cancers is immune-activated, with PD-L1 expression and/or TILs in the tumor microenvironment. The PD-1 inhibitor pembrolizumab in combination with chemotherapy is now approved by the US FDA for the first-line treatment of metastatic PD-L1 + triple negative breast cancer, and the PD-L1 inhibitor atezolizumab has also demonstrated clinical activity. The median progression-free survival for pembrolizumab or atezolizumab combined with chemotherapy increased with the addition of immunotherapy by 4.1 months and 2.5 months, respectively. Despite this success, there is major room for improvement. Clinical benefit is modest. Only about 40% of triple negative breast cancers are PD-L1 + , not all PD-L1 + patients with advanced triple negative breast cancer respond, and immunotherapy is not yet approved for advanced PD-L1-negative triple negative breast cancer, HER2 + breast cancer, or ER + breast cancer. It is likely that redundant pathways of immune suppression are active in breast cancer, or that important pathways of immune activation are silent. In this review, we discuss emerging strategies for targeting multiple pathways of immunoregulation in advanced breast cancer with dual immune checkpoint inhibition, bispecific antibodies, and novel antibody drug conjugates. We also discuss the potential of nanotechnology to improve the delivery of immunotherapeutics to the breast tumor microenvironment to enhance their antitumor activity.
乳腺癌在历史上被认为是非免疫原性肿瘤。过去 10-15 年的多项研究表明，一小部分乳腺癌具有免疫激活特性，肿瘤微环境中存在 PD-L1 表达和/或肿瘤浸润淋巴细胞（TILs）。目前，美国食品药品监督管理局（FDA）已批准 PD-1 抑制剂帕博利珠单抗联合化疗用于治疗转移性 PD-L1 阳性、三阴性乳腺癌的一线治疗，PD-L1 抑制剂阿替利珠单抗也显示出临床疗效。与化疗联合应用时，帕博利珠单抗或阿替利珠单抗的中位无进展生存期分别延长了 4.1 个月和 2.5 个月。尽管取得了这些成功，但仍有很大的改进空间。临床获益有限。只有约 40%的三阴性乳腺癌为 PD-L1 阳性，并非所有晚期三阴性乳腺癌 PD-L1 阳性患者都有应答，免疫疗法尚未获批用于晚期 PD-L1 阴性三阴性乳腺癌、HER2 阳性乳腺癌或 ER 阳性乳腺癌。在乳腺癌中，可能存在冗余的免疫抑制途径活跃，或者重要的免疫激活途径处于沉默状态。在这篇综述中，我们讨论了用双重免疫检查点抑制、双特异性抗体和新型抗体药物偶联物靶向晚期乳腺癌中多个免疫调节途径的新策略。我们还讨论了纳米技术在提高免疫治疗药物在乳腺肿瘤微环境中的递送以增强其抗肿瘤活性方面的潜力。
