抗 PD-1 治疗晚期黑色素瘤患者的活检主要病理反应（MPRbx）：对治疗反应的早期、实时生物标志物的证据。
Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.
机构信息
Departments of Dermatology.
Biostatistics, Johns Hopkins University SOM, Baltimore; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins, Baltimore.
出版信息
Ann Oncol. 2019 Apr 1;30(4):589-596. doi: 10.1093/annonc/mdz019.
BACKGROUND
With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.
MATERIALS AND METHODS
Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).
RESULTS
Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients.
CONCLUSIONS
Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.
背景
随着抗 PD-1 疗法在黑色素瘤和其他肿瘤类型患者中的应用不断增加，人们对开发与长期患者预后相关的早期治疗生物标志物产生了兴趣。了解免疫介导的肿瘤消退的病理特征是这方面工作的关键。
材料和方法
在一项黑色素瘤晚期患者的预治疗和治疗期间标本的发现队列中，通过苏木精和伊红（H&E）染色切片确定了抗 PD-1 治疗后免疫相关病理反应（irPR）的组织学特征。这些特征用于生成 irPR 评分[从 0（无 irPR 特征）到 3（活检主要病理反应（MPRbx），残留存活肿瘤≤10%）]。然后，在黑色素瘤患者接受nivolumab 单药治疗的 CA209-038（NCT01621490）前瞻性收集的预治疗和治疗期间活检的验证队列中，通过 RECIST1.1 和总生存来测试该评分系统与客观反应的相关性。
结果
与无反应者相比，发现队列中应答者的标本具有免疫激活（中等至高 TIL 密度、浆细胞）和伤口愈合/组织修复（新生血管形成、增殖性纤维化）特征（每项特征 P≤0.021）。在验证队列中，irPR 评分增加与客观反应相关（P=0.009），MPRbx 与总生存时间延长相关（n=51；HR0.13；95%CI，0.054-0.31，P=0.015）。肿瘤坏死或预处理组织学特征均与反应无关。16 例稳定疾病患者中有 8 例（50%）显示 irPR 特征，其中 2 例为 MPRbx，这表明对于一些患者，在治疗 4 周时，病理和影像学特征之间存在不匹配。
结论
来自晚期黑色素瘤患者的常规 H&E 染色活检切片中免疫介导的肿瘤消退特征与抗 PD-1 治疗的客观反应和总生存率相关。在治疗期间进行活检可能对有影像学稳定疾病的患者的治疗决策特别具有临床意义。这种方法成本低、简单、广泛可用。
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