Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia.
J Natl Cancer Inst. 2023 Jul 6;115(7):805-814. doi: 10.1093/jnci/djad072.
Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy.
We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors.
In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone.
Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.
程序性细胞死亡受体 1（PD-1）和程序性细胞死亡配体 1（PD-L1）抑制剂在曲妥珠单抗耐药的晚期 HER2 阳性乳腺癌患者中的疗效不佳。Tucatinib 是一种有效的、选择性的抗 HER2 酪氨酸激酶抑制剂，在曲妥珠单抗耐药的晚期患者中具有显著的临床获益。我们研究了 tucatinib 是否可以改变肿瘤微环境，以及是否可以利用这一点来提高治疗效果。
我们使用 2 种免疫功能正常的、HER2 阳性的鼠乳腺癌模型（曲妥珠单抗敏感的 H2N113；曲妥珠单抗耐药的 Fo5）来研究 tucatinib 的抗肿瘤疗效和免疫反应的贡献，并研究了 tucatinib 与曲妥珠单抗和 PD-1 或 PD-L1 检查点抑制剂联合使用的疗效。
在这两种模型中，tucatinib 均能显著抑制肿瘤生长，并呈现出剂量依赖性的疗效。通过对用 tucatinib 治疗的小鼠肿瘤浸润淋巴细胞进行流式细胞术的体外分析显示，CD8+效应记忆 T 细胞的频率增加、增殖增强、效应功能增强。Tucatinib 治疗还增加了 CD8+PD-1+和 CD8+TIM3+T 细胞、CD49+自然杀伤细胞、单核细胞、树突状细胞和巨噬细胞上的主要组织相容性复合体 II 的表达，并减少了髓系来源的抑制细胞。基因表达分析显示，与免疫激活、I 型和 II 型干扰素反应、适应性免疫反应和抗原受体信号相关的途径显著富集。在体内，与单独使用 tucatinib 相比，tucatinib 与 α-PD-L1 或 α-PD-1 联合使用可显著提高小鼠的疗效并延长其生存时间。
Tucatinib 可有效地调节免疫微环境，与 α-PD-L1 或 α-PD-1 的联合治疗在 HER2 阳性肿瘤模型中显示出更高的疗效。这些发现为在临床上研究 tucatinib 和免疫检查点抑制提供了依据。
