Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
National Cancer Center Hospital East, Kashiwa, Seattle, WA, United States.
Front Immunol. 2022 Aug 2;13:897991. doi: 10.3389/fimmu.2022.897991. eCollection 2022.
Clinical/translational cancer immunotherapy.
The goal of this study was to estimate the objective response rate for utomilumab in adults with immune checkpoint inhibitor (ICI)-refractory melanoma and non-small-cell lung cancer (NSCLC).
Utomilumab was dosed intravenously every 4 weeks (Q4W) and adverse events (AEs) monitored. Tumor responses by RECIST1.1 were assessed by baseline and on-treatment scans. Tumor biopsies were collected for detection of programmed cell death ligand 1, CD8, 4-1BB, perforin, and granzyme B, and gene expression analyzed by next-generation sequencing. CD8+ T cells from healthy donors were stimulated with anti-CD3 ± utomilumab and compared with control.
Patients with melanoma (n=43) and NSCLC (n=20) received utomilumab 0.24 mg/kg (n=36), 1.2 mg/kg (n=26), or 10 mg/kg (n=1). Treatment-emergent AEs (TEAEs) occurred in 55 (87.3%) patients and serious TEAEs in 18 (28.6%). Five (7.9%) patients discontinued owing to TEAEs. Thirty-two (50.8%) patients experienced treatment-related AEs, mostly grade 1-2. Objective response rate: 2.3% in patients with melanoma; no confirmed responses for patients with NSCLC. Ten patients each with melanoma (23.3%) or NSCLC (50%) had stable disease; respective median (95% confidence interval, CI) progression-free survival was 1.8 (1.7-1.9) and 3.6 (1.6-6.5) months. Utomilumab exposure increased with dose. The incidences of antidrug and neutralizing antibodies were 46.3% and 19.4%, respectively. Efficacy was associated with immune-active tumor microenvironments, and pharmacodynamic activity appeared to be blunted at higher doses.
Utomilumab was well tolerated, but antitumor activity was low in patients who previously progressed on ICIs. The potential of 4-1BB agonists requires additional study to optimize efficacy while maintaining the tolerable safety profile.
临床/转化癌症免疫疗法。
本研究的目的是评估utomilumab 治疗对免疫检查点抑制剂（ICI）难治性黑色素瘤和非小细胞肺癌（NSCLC）成人患者的客观缓解率。
utomilumab 静脉输注，每 4 周一次（Q4W），监测不良事件（AE）。根据基线和治疗期间的扫描评估 RECIST1.1 肿瘤反应。采集肿瘤活检以检测程序性死亡配体 1、CD8、4-1BB、穿孔素和颗粒酶 B，并通过下一代测序分析基因表达。用抗 CD3 ±utomilumab 刺激健康供体的 CD8+T 细胞，并与对照进行比较。
接受 utomilumab 0.24mg/kg（n=36）、1.2mg/kg（n=26）或 10mg/kg（n=1）的黑色素瘤（n=43）和 NSCLC（n=20）患者出现治疗相关不良事件（TEAE），发生率为 55（87.3%），严重 TEAEs 发生率为 18（28.6%）。因 TEAEs 停药的有 5（7.9%）例。32（50.8%）例患者出现治疗相关 AEs，多数为 1-2 级。黑色素瘤患者的客观缓解率为 2.3%；无 NSCLC 患者的确认缓解。黑色素瘤和 NSCLC 患者各有 10 例患者（23.3%和 50%）疾病稳定；相应的中位（95%置信区间，CI）无进展生存期分别为 1.8（1.7-1.9）和 3.6（1.6-6.5）个月。utomilumab 暴露量随剂量增加而增加。抗药物和中和抗体的发生率分别为 46.3%和 19.4%。疗效与免疫活性肿瘤微环境相关，药物动力学活性在较高剂量下似乎减弱。
utomilumab 耐受性良好，但在 ICI 治疗后进展的患者中抗肿瘤活性较低。4-1BB 激动剂的潜力需要进一步研究，以在保持可耐受的安全性特征的同时提高疗效。
