肿瘤细胞治疗研究
英文原题：Biomarkers of activity from a phase I study of cergutuzumab amunaleukin in patients with advanced solid tumors.
在转移性/不可切除 CEA⁺ 实体瘤患者中，CA 诱导外周血和肿瘤微环境中的免疫药效学效应，而不会优先激活 Treg 细胞。
背景：Cergutuzumab amunaleukin（CA）是一种免疫细胞因子，由抗癌胚抗原（CEA）抗体与白细胞介素-2（IL-2）变体连接而成。CA不结合CD25（IL-2受体α），设计目的是维持对T细胞和自然杀伤（NK）细胞的刺激作用，同时避免刺激调节性T细胞（Treg）。既往小鼠模型研究显示，与野生型IL-2相比，CA对CEA表面表达阳性（CEA⁺）肿瘤的靶向性更强，并提高外周血和肿瘤组织中的CD8⁺ T细胞及NK细胞数量。本文报告首个人体开放标签、多中心I期剂量递增研究的生物标志物数据，该研究考察CA用于转移性/不可切除CEA⁺实体瘤患者（NCT02004106）。 方法：患者每周静脉注射递增剂量CA（6/10/20 mg），或每2周注射一次（10/20/30/40 mg）。采用流式细胞术测定循环中CD4⁺和CD8⁺ T细胞、NK细胞、巨噬细胞/单核细胞、Treg和B细胞的绝对数量（个/mL），并检测其活化和增殖标志物表达。对治疗前及治疗期间的连续配对肿瘤活检样本进行流式细胞术、多重免疫组织化学和整体RNA测序。并以抗肿瘤活性开展相关性分析。 结果：共收集55例患者的生物标志物数据。治疗后外周血中增殖中的NK细胞、CD8⁺ T细胞和CD4⁺ T细胞均增加，未见明显剂量效应。中、高剂量CA治疗期间，循环可溶性CD25水平升高；高剂量CA时，肿瘤坏死因子等细胞因子水平也升高。治疗期间肿瘤样本中的CD8⁺ T细胞总量和增殖细胞增加，CD3⁺穿孔素⁺ T细胞亦增加；重要的是，Treg未增加。每周给药较每2周给药更显著提高CD8⁺/CD4⁺ T细胞比值，而每2周给药方案中PD-L1阳性CD14⁺细胞增加更明显。治疗期间循环细胞因子水平较高与更长的无进展生存期（PFS）相关。除与NK细胞密度呈正相关外，PFS与肿瘤浸润免疫细胞群未见其他相关性。 结论：在转移性/不可切除CEA⁺实体瘤患者中，CA可在外周血和肿瘤微环境中诱导免疫药效学效应，而未优先激活Treg。 试验注册号：NCT02004106；BP28920。
BACKGROUND: Cergutuzumab amunaleukin (CA) is an immunocytokine comprising an anticarcinoembryonic antigen (CEA) linked to an interleukin-2 (IL-2) variant. CA does not bind to CD25 (IL-2 receptor ) and was designed to maintain the T and natural killer (NK) cell stimulatory effect, while avoiding stimulating effects on regulatory T cells (Tregs). In mouse models, CA previously demonstrated superior tumor targeting to CEA surface expression-positive (CEA+) tumors and increased CD8+ T cells and NK cell numbers in peripheral blood and tumor tissue when compared with wild-type IL-2. We present biomarker data from the first-in-human, open-label, multicenter, phase I, dose-escalation study investigating CA in patients with metastatic/unresectable CEA+ solid tumors (NCT02004106). METHODS: Patients received ascending doses of CA intravenously weekly (qw: 6/10/20 mg) or every 2 weeks (q2w: 10/20/30/40 mg). Flow cytometry determined absolute numbers/mL of CD4+ and CD8+ T cells, NK cells, macrophages/monocytes, Tregs, and B cells and their expression of activation and proliferation markers in circulation. Sequential pretreatment and on-treatment paired tumor biopsies were studied by flow cytometry, multicolor immunohistochemistry, and bulk RNA sequencing. Antitumor activity was used for correlative studies. RESULTS: Biomarker data were collected from 55 patients. After treatment, peripheral blood samples showed increased proliferating NK cells, CD8+ T cells, and CD4+ T cells, without an apparent dose effect. Levels of circulating soluble CD25 increased in patients with intermediate/high CA doses on-treatment; levels of cytokines, such as tumor necrosis factor, also increased with high CA dose levels. On-treatment tumor samples showed increases in total and proliferating CD8+ T cells as well as CD3+ perforin+ T cells but, importantly, not in Tregs. Notably, increases in the ratio of CD8+/CD4+ T cells were more pronounced for qw than for q2w dosing, while programmed death ligand-1-positive CD14+ cells increased, particularly for the q2w schedule. Higher on-treatment circulating levels of cytokines correlated with longer progression-free survival (PFS). Apart from the positive correlation with NK cell density, no other correlations between PFS and infiltrating immune cell populations in the tumor were observed. CONCLUSIONS: CA-induced immune pharmacodynamic effects in peripheral blood and in the tumor microenvironment without preferential Treg cell activation in patients with metastatic/unresectable CEA+ solid tumors. TRIAL REGISTRATION NUMBER: NCT02004106; BP28920.
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