腹腔内 CMP-001：一种用于治疗胃肠道和胰腺胆道癌腹膜转移的新型免疫疗法。
Intraperitoneal CMP-001: A Novel Immunotherapy for Treating Peritoneal Carcinomatosis of Gastrointestinal and Pancreaticobiliary Cancer.
机构信息
Department of Surgery, University of Iowa Hospitals and Clinics, University of Iowa, Iowa City, IA, USA.
Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
出版信息
Ann Surg Oncol. 2021 Feb;28(2):1187-1197. doi: 10.1245/s10434-020-08591-7. Epub 2020 May 14.
BACKGROUND
The treatment options for patients with peritoneal carcinomatosis (PC) of gastrointestinal and pancreaticobiliary origins are limited. The virus-like particle, CMP-001, composed of the Qβ bacteriophage capsid protein encapsulating a CpG-A oligodeoxynucleotide, activates plasmacytoid dendritic cells (pDCs) and triggers interferon alpha (IFNα) release, leading to a cascade of anti-tumor immune effects.
METHODS
To evaluate the ability of CMP-001 to trigger an immune response in patients with PC, peritoneal cells were isolated and stimulated ex vivo with CMP-001. Both IFNα release and percentage of pDC were quantified using enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. To evaluate the anti-tumor response in vivo, murine PC models were generated using mouse cancer cell lines (Panc02 and MC38) in immunocompetent mice treated with intraperitoneal CMP-001 or saline control. Survival was followed, and the immunophenotype of cells in the peritoneal tumor microenvironment was evaluated.
RESULTS
The pDCs accounted for 1% (range 0.1-3.9%; n = 17) of the isolated peritoneal cells. Ex vivo CMP-001 stimulation of the peritoneal cells released an average of 0.77 ng/ml of IFNα (range, 0-4700 pg/ml; n = 14). The IFNα concentration was proportional to the percentage of pDCs present in the peritoneal cell mixture (r = 0.6; p = 0.037). In murine PC models, intraperitoneal CMP-001 treatment elicited an anti-tumor immune response including an increase in chemokines (RANTES and MIP-1β), pro-inflammatory cytokines (IFNγ, interleukin 6 [IL-6], and IL-12), and peritoneal/tumor immune infiltration (CD4/CD8 T and natural killer [NK] cells). The CMP-001 treatment improved survival in both the Panc02 (median, 35 vs 28 days) and the MC38 (median: 57 vs 35 days) PC models (p < 0.05).
CONCLUSIONS
As a novel immunotherapeutic agent, CMP-001 may be effective for treating patients with PC.
背景
胃肠道和胰腺胆道来源的腹膜癌患者的治疗选择有限。病毒样颗粒 CMP-001 由 Qβ噬菌体衣壳蛋白组成，可包裹 CpG-A 寡脱氧核苷酸，激活浆细胞样树突状细胞（pDC）并触发干扰素-α（IFNα）释放，从而引发一连串的抗肿瘤免疫效应。
方法
为了评估 CMP-001 引发 PC 患者免疫反应的能力，分离腹膜细胞并在体外用 CMP-001 刺激。分别使用酶联免疫吸附测定（ELISA）和流式细胞术定量测定 IFNα 释放和 pDC 的百分比。为了评估体内抗肿瘤反应，使用免疫活性小鼠中的小鼠癌细胞系（Panc02 和 MC38）在腹腔内给予 CMP-001 或盐水对照后生成 PC 模型。跟踪生存情况，并评估腹膜肿瘤微环境中细胞的免疫表型。
结果
pDC 占分离的腹膜细胞的 1%（范围 0.1-3.9%；n=17）。体外 CMP-001 刺激腹膜细胞平均释放 0.77ng/ml IFNα（范围 0-4700pg/ml；n=14）。IFNα 浓度与腹膜细胞混合物中存在的 pDC 百分比成正比（r=0.6；p=0.037）。在小鼠 PC 模型中，腹腔内 CMP-001 治疗引发了抗肿瘤免疫反应，包括趋化因子（RANTES 和 MIP-1β）、促炎细胞因子（IFNγ、白细胞介素 6 [IL-6]和白细胞介素 12）以及腹膜/肿瘤免疫浸润（CD4/CD8 T 和自然杀伤 [NK]细胞）的增加。CMP-001 治疗改善了两种 PC 模型（Panc02：中位 35 天与 28 天；MC38：中位 57 天与 35 天）的生存（p<0.05）。
结论
作为一种新型免疫治疗药物，CMP-001 可能对治疗 PC 患者有效。
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