Aronson S L, Thijssen B, Lopez-Yurda M, Koole S N, van der Leest P, León-Castillo A, Harkes R, Seignette I M, Sanders J, Alkemade M, Kemper I, Holtkamp M J, Mandjes I A M, Broeks A, Lahaye M J, Rijlaarsdam M A, van den Broek D, Wessels L F A, Horlings H M, van Driel W J, Sonke G S
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Center for Gynecologic Oncology Amsterdam, Department of Gynecologic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Nat Commun. 2025 Apr 14;16(1):3520. doi: 10.1038/s41467-025-58440-y.
While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian cancer (HGSOC) remains limited. Some patients, however, achieve lasting responses, emphasizing the need to understand how tumor microenvironment and molecular characteristics influence ICI response. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated stage IV HGSOC patients, who were scheduled for 6 cycles of carboplatin-paclitaxel and interval cytoreductive surgery. Pembrolizumab (pembro) was added from cycle two and continued for one year. The primary objective was to assess intratumoral immune activation using multiplexed immunofluorescence and immune-related gene expression. Our findings show immune activation, evidenced by an increase in CD3 + , CD8 + , CD8 + /FOXP3+ ratio, TNF-α and interferon-γ signaling. Treatment was well-tolerated. We observed major pathologic responses in 9/33 patients (27%, 95%CI 14-46), with pathologic response strongly associated with immune activation and OS. At a median follow-up of 52.8 months, 8/9 major responders were alive, with 6 patients recurrence-free. In contrast, 4/24 minor responders survived, including one recurrence-free. ctDNA clearance was observed in all major responders and was associated with prolonged PFS and OS. PD-L1 expression and homologous recombination deficiency were predictive of major response and may serve as biomarkers, warranting further exploration. These results suggest major responders may benefit from neo-adjuvant pembro.
虽然免疫检查点抑制剂（ICI）彻底改变了癌症治疗方式，但其在高级别浆液性卵巢癌（HGSOC）中的疗效仍然有限。然而，一些患者实现了持久缓解，这凸显了了解肿瘤微环境和分子特征如何影响ICI反应的必要性。2期Neo-Pembro研究（NCT03126812）纳入了33例未经治疗的IV期HGSOC患者，这些患者计划接受6个周期的卡铂-紫杉醇化疗以及间隔减瘤手术。从第2周期开始加用帕博利珠单抗（pembro），并持续使用一年。主要目的是使用多重免疫荧光和免疫相关基因表达来评估肿瘤内免疫激活情况。我们的研究结果显示出免疫激活，表现为CD3 +、CD8 +、CD8 + / FOXP3 +比值、TNF-α和干扰素-γ信号增加。治疗耐受性良好。我们在9/33例患者（27%，95%CI 14-46）中观察到主要病理反应，病理反应与免疫激活和总生存期密切相关。在中位随访52.8个月时，9例主要反应者中有8例存活，6例无复发。相比之下，24例次要反应者中有4例存活，其中1例无复发。在所有主要反应者中均观察到循环肿瘤DNA（ctDNA）清除，并且与延长的无进展生存期和总生存期相关。PD-L1表达和同源重组缺陷可预测主要反应，可能作为生物标志物，值得进一步探索。这些结果表明主要反应者可能从新辅助pembro治疗中获益。
