Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, MS8117, Aurora, CO, 80045, USA.
University of Colorado Cancer Center, Anschutz Medical Campus, 12801 E 17th Ave, MS8117, Aurora, CO, 80045, USA.
BMC Cancer. 2020 Nov 4;20(1):1063. doi: 10.1186/s12885-020-07500-1.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.
Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2Il2rγSIRPα (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells.
The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01).
Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，其系统治疗选择有限。RX-5902 是一种新型抗癌药物，可抑制磷酸化-p68，从而减弱核 β-连环蛋白信号传导。本研究的目的是评估 β-连环蛋白信号传导阻断增强免疫检查点抑制剂抗 CTLA-4 和抗 PD-1 在免疫活性的 TNBC 临床前模型中的疗效。
在注射 4T1 TNBC 细胞系的 BALB/c 小鼠中，研究了 RX-5902、抗 PD-1、抗 CTLA-4 或联合用药的治疗效果。将人源化 BALB/c-Rag2Il2rγSIRPα（hu-CB-BRGS）小鼠移植了人类免疫系统，并植入 MDA-MB-231 细胞。根据人类造血嵌合体，将小鼠随机分为治疗组，并接受 RX-5902、抗 PD-1 或联合治疗。处死时，采集骨髓、淋巴结、脾脏和肿瘤，用于流式细胞术分析人免疫细胞。
在 4T1 和人类免疫系统和 MDA-MB-231 异种移植模型中，加用 RX-5902 可减少肿瘤生长。免疫分析表明，与载体相比，RX-5902 治疗可使肿瘤浸润淋巴细胞（TILs）中激活的 T 细胞数量显著增加（p<0.05）。在 RX-5902/纳武单抗联合组中，TILs 中的 CD4+T 细胞百分比显著增加，全身性颗粒酶 B 产生增加（p<0.01）。
RX-5902 增强了 nivolumab 在 TNBC 临床前模型中的疗效。用 RX-5902 和联合用药治疗的小鼠中观察到免疫谱的几个变化，包括激活的 TILs 增加和人类髓系群体减少，这通常与肿瘤微环境中的免疫抑制有关。RX-5902 还显示出在 4T-1 鼠 TNBC 模型中增强 CTLA4 和 PD-1 抑制剂检查点抑制剂的作用。这些发现表明，当与检查点抑制剂联合使用时，RX-5902 可能在 TNBC 中具有重要的免疫调节和抗肿瘤活性。
