CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Phase I Trial Combining Chemokine-Targeting with Loco-Regional Chemoimmunotherapy for Recurrent, Platinum-Sensitive Ovarian Cancer Shows Induction of CXCR3 Ligands and Markers of Type 1 Immunity.
Phase I Trial Combining Chemokine-Targeting with Loco-Regional Chemoimmunotherapy for Recurrent, Platinum-Sensitive Ovarian Cancer Shows Induction of CXCR3 Ligands and Markers of Type 1 Immunity.
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趋化因子调节性腹腔内 CITC 安全、可耐受，并与有利于 CTL 趋化和功能的 ISG 变化相关。该联合方案（加 DC 疫苗）将在 II 期试验中进行测试。参见 Aranda 等人的相关评论，第 1993 页。
肿瘤微环境（TME）中细胞毒性T淋巴细胞（CTL）丰度增加预示上皮性卵巢癌（EOC）患者预后良好，而调节性T细胞（Treg）则预示预后不良。基于TLR3配体、IFNα和COX-2阻断剂在选择性增强CTL趋化因子、抑制Treg趋化因子方面的协同活性，我们测试了一种新型腹腔化疗免疫联合方案（CITC），以评估其在复发性EOC患者中的耐受性及对TME的调节作用。
12例患者入组NCT02432378试验的I期部分，接受腹腔内顺铂、腹腔内rintatolimod（dsRNA，TLR3配体）和口服塞来昔布（COX-2阻断剂）治疗。队列2、3和4的患者还分别接受2、6和18百万单位（MU）的腹腔内IFNα。主要目标是评估安全性、确定2期推荐剂量（P2RD）以及表征免疫TME的变化。分别通过NanoString和Meso Scale Discovery（MSD）多重检测对腹腔驻留细胞和腹腔冲洗液进行分析。
IFNα的P2RD为6 MU。中位无进展生存期和总生存期分别为8.4个月和30个月。通过腹腔冲洗对腹膜腔进行纵向采样，显示IFN刺激基因（ISG）局部上调，包括CTL吸引趋化因子（CXCL-9、-10、-11）、MHC I/II、穿孔素和颗粒酶。这些变化在趋化因子调节后2天出现，并在1周内消退。
Increased prevalence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts positive outcomes in patients with epithelial ovarian cancer (EOC), whereas the regulatory T cells (Treg) predict poor outcomes. Guided by the synergistic activity of TLR3 ligands, IFNα, and COX-2 blockers in selectively enhancing CTL-attractants but suppressing Treg-attractants, we tested a novel intraperitoneal chemoimmunotherapy combination (CITC), to assess its tolerability and TME-modulatory impact in patients with recurrent EOC.
Twelve patients were enrolled in phase I portion of the trial NCT02432378, and treated with intraperitoneal cisplatin, intraperitoneal rintatolimod (dsRNA, TLR3 ligand), and oral celecoxib (COX-2 blocker). Patients in cohorts 2, 3, and 4 also received intraperitoneal IFNα at 2, 6, and 18 million units (MU), respectively. Primary objectives were to evaluate safety, identify phase 2 recommended dose (P2RD), and characterize changes in the immune TME. Peritoneal resident cells and intraperitoneal wash fluid were profiled via NanoString and Meso Scale Discovery (MSD) multiplex assay, respectively.
The P2RD of IFNα was 6 MU. Median progression-free survival and overall survival were 8.4 and 30 months, respectively. Longitudinal sampling of the peritoneal cavity via intraperitoneal washes demonstrated local upregulation of IFN-stimulated genes (ISG), including CTL-attracting chemokines (CXCL-9, -10, -11), MHC I/II, perforin, and granzymes. These changes were present 2 days after chemokine modulation and subsided within 1 week.
The chemokine-modulating intraperitoneal-CITC is safe, tolerable, and associated with ISG changes that favor CTL chemoattraction and function. This combination (plus DC vaccine) will be tested in a phase II trial. See related commentary by Aranda et al., p. 1993.
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