Levine Cancer Institute, Atrium Health, 1021 Morehead Medical Drive, Charlotte, NC, 28204, USA.
Baylor University Medical Center, Texas Oncology Dallas, US Oncology Research, 3410 Worth Street, Suite 400, Dallas, TX, 75246, USA.
Breast Cancer Res Treat. 2023 Sep;201(2):307-316. doi: 10.1007/s10549-023-07009-8. Epub 2023 Jul 7.
In a phase II trial in patients with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb) enhanced T-cell activation and improved overall survival versus GCb alone. The survival benefit was more pronounced in patients with higher immune-related gene expression. We assessed immune cell subsets and used molecular profiling to further elucidate effects on antitumor immunity.
Patients with mTNBC and ≤ 2 prior chemotherapy regimens for locally recurrent TNBC or mTNBC were randomized 1:1:1 to GCb on days 1 and 8, trilaciclib prior to GCb on days 1 and 8, or trilaciclib alone on days 1 and 8, and prior to GCb on days 2 and 9. Gene expression, immune cell populations, and Tumor Inflammation Signature (TIS) scores were assessed in baseline tumor samples, with flow cytometric analysis and intracellular and surface cytokine staining used to assess immune cell populations and function.
After two cycles, the trilaciclib plus GCb group (n = 68) had fewer total T cells and significantly fewer CD8+ T cells and myeloid-derived suppressor cells compared with baseline, with enhanced T-cell effector function versus GCb alone. No significant differences were observed in patients who received GCb alone (n = 34). Of 58 patients in the trilaciclib plus GCb group with antitumor response data, 27 had an objective response. RNA sequencing revealed a trend toward higher baseline TIS scores among responders versus non‑responders.
The results suggest that administering trilaciclib prior to GCb may modulate the composition and response of immune cell subsets to TNBC.
在转移性三阴性乳腺癌（mTNBC；NCT02978716）患者的 II 期试验中，与单独接受吉西他滨加卡铂（GCb）治疗相比，在接受吉西他滨加卡铂治疗前给予替拉西利可增强 T 细胞激活并改善总体生存。在免疫相关基因表达较高的患者中，生存获益更为显著。我们评估了免疫细胞亚群，并使用分子谱分析进一步阐明其对抗肿瘤免疫的影响。
患有 mTNBC 和局部复发性 TNBC 或 mTNBC 的最多 2 次既往化疗方案的患者按 1:1:1 的比例随机分为 GCb 组（第 1 和第 8 天）、替拉西利联合 GCb 组（第 1 和第 8 天）和替拉西利单药组（第 1 和第 8 天），GCb 前 2 天和第 9 天。基线肿瘤样本评估基因表达、免疫细胞群和肿瘤炎症特征（TIS）评分，采用流式细胞术分析和细胞内及表面细胞因子染色评估免疫细胞群和功能。
在两个周期后，与基线相比，替拉西利联合 GCb 组（n=68）总 T 细胞减少，CD8+T 细胞和髓系来源抑制细胞显著减少，与单独接受 GCb 治疗的患者相比，T 细胞效应功能增强。单独接受 GCb 治疗的患者（n=34）未观察到显著差异。在接受替拉西利联合 GCb 治疗且有抗肿瘤反应数据的 58 例患者中，有 27 例有客观反应。RNA 测序显示，与无反应者相比，反应者的基线 TIS 评分有升高的趋势。
结果表明，在接受 GCb 治疗前给予替拉西利可能调节 TNBC 中免疫细胞亚群的组成和反应。
