CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Beyond the "cold" barrier: Redefining the clinical paradigm of immune checkpoint inhibitor therapy in ovarian cancer.
Beyond the "cold" barrier: Redefining the clinical paradigm of immune checkpoint inhibitor therapy in ovarian cancer.
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卵巢癌仍然是一种免疫学上的“冷”肿瘤，尽管其具有潜在的免疫原性，但早期全人群免疫检查点抑制剂（ICI）试验大多为阴性。本综述采取以临床医生为中心、按分期划分的视角，将方案选择、治疗线数与肿瘤免疫背景同观察到的结局相联系。在新辅助和一线治疗背景下，未加选择的ICI联合化疗及抗血管生成药物未能改善无进展生存期，而在生物标志物富集队列中，将聚（ADP-核糖）聚合酶（PARP）抑制剂加入ICI维持治疗取得了适度获益。在复发疾病中，单药ICI产生的客观缓解率为8-15%，且大多数随机联合试验为阴性。在铂耐药疾病中进行的III期KEYNOTE-B96试验显示，当帕博利珠单抗与每周紫杉醇联合、伴或不伴贝伐珠单抗时，在意向治疗人群中观察到无进展生存期获益，在程序性死亡配体1（PD-L1）联合阳性评分≥1的肿瘤中观察到总生存期获益，这强调了在更早线数中免疫调节性化疗骨架的价值。卵巢透明细胞癌显现为一种免疫治疗敏感、化疗耐药的亚型，值得专门分层。
我们解释了为何单分析物生物标志物——PD-L1、肿瘤突变负荷、同源重组缺陷/BRCA1/2——未能可靠地富集获益，并概述了一种多维方法，整合基因组瘢痕（例如突变特征3）、免疫功能状态（Immunoscore、CD8⁺TIL（肿瘤浸润淋巴细胞）密度及CD8⁺：调节性T细胞比值）和空间结构（炎症型、排斥型、荒漠型表型）。该框架旨在超越全人群时代，迈向卵巢癌中基于背景信息的精准免疫治疗。
Ovarian cancer remains an immunologically "cold" tumor, with early all-comer immune checkpoint inhibitor (ICI) trials largely negative despite underlying immunogenicity. This review takes a clinician-centric, stage-specific view linking regimen choice, treatment line, and tumor-immune context to observed outcomes. In the neoadjuvant and first-line settings, unselected ICI combinations with chemotherapy and anti-angiogenic agents failed to improve progression-free survival, whereas adding a poly (ADP-ribose) polymerase (PARP) inhibitor to ICI maintenance yielded modest gains in biomarker-enriched cohorts.
In recurrent disease, single-agent ICIs produced objective response rates of 8-15%, and most randomized combinations were negative.
The phase III KEYNOTE-B96 trial in platinum-resistant disease demonstrated a progression-free survival benefit in the intention-to-treat population and an overall survival benefit in tumors with programmed death ligand 1 (PD-L1) combined positive score ≥ 1 when pembrolizumab was paired with weekly paclitaxel with or without bevacizumab, underscoring the value of an immunomodulatory chemotherapy backbone in earlier lines. Ovarian clear cell carcinoma emerges as an immunotherapy-sensitive, chemo-resistant subtype that warrants dedicated stratification.
We explain why single-analyte biomarkers-PD-L1, tumor mutational burden, homologous recombination deficiency/BRCA1/2-have not reliably enriched benefit and outline a multidimensional approach integrating genomic scars (e. g. , mutational signature 3), immune functional state (Immunoscore, CD8⁺ tumor-infiltrating lymphocyte density and CD8⁺: regulatory T-cell ratio), and spatial architecture (inflamed, excluded, desert phenotypes). This framework aims to move beyond the all-comer era toward context-informed precision immunotherapy in ovarian cancer.
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