肿瘤细胞治疗研究
英文原题：First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors.
NEO-201 在 1.5 mg/kg 的最大耐受剂量下安全且耐受性良好，中性粒细胞减少是最常见的不良事件。
背景：NEO-201是一种人源化IgG1单克隆抗体，针对结直肠癌患者肿瘤相关抗原，可结合靶细胞表达的核心1或延伸核心1型O-聚糖。本研究报告其在标准治疗无效晚期实体瘤患者中的I期试验结果。方法：单中心、开放标签3+3剂量递增研究，每两周静脉给药一次，每周期28天，剂量为1、1.5或2 mg/kg，直至剂量限制性毒性、进展或退出。主要目标为确定最大耐受剂量和II期推荐剂量，次要目标为按RECIST 1.1评估抗肿瘤活性，并探索药代动力学、免疫指标及其与临床反应的关系。结果：纳入17人（结直肠癌11例、胰腺癌4例、乳腺癌2例），2人首剂后退出，无法评估剂量限制性毒性。15名安全性可评估者中12人因疾病进展停药，3人因剂量限制性毒性停药。共给药69次，中位数4次。常见3/4级毒性为中性粒细胞减少、白细胞减少和淋巴细胞减少。13人可评估疗效，4例结直肠癌患者最佳疗效为疾病稳定。基线可溶性MICA较高与NK细胞活化标志降低和疾病进展相关。流式检测意外发现NEO-201也结合循环Treg，疾病稳定患者中这类细胞数量下降尤为明显。结论：NEO-201在1.5 mg/kg最大耐受剂量下安全且耐受良好，中性粒细胞减少最常见。治疗后Treg比例下降支持正在开展的II期研究，评估NEO-201与帕博利珠单抗联合治疗难治性实体瘤。
BACKGROUND: NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. METHODS: This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. RESULTS: Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1-15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. CONCLUSIONS: NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. TRIAL REGISTRATION: NCT03476681 . Registered 03/26/2018.
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