KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150–180 mg/m2) and pelareorep (1 × 1010 TCID50–3 × 1010 TCID50)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1–5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naïve patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m2 irinotecan) and pelareorep (3 × 1010 TCID50) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid σ-1 protein demonstrated viral “homing” in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.

中文翻译：

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在 KRAS 突变型结直肠癌患者的 I 期试验中阐明呼肠孤病毒药效学

KRAS 突变是转移性结直肠癌 (mCRC) 患者抗 EGFR 药物的阴性预测生物标志物，并且仍然是一个难以捉摸的目标。Pelareorep 是一种双链 RNA 病毒，可在 KRAS 突变的细胞中选择性复制，并与伊立替康协同作用。FOLFIRI/贝伐珠单抗 [伊立替康 (150–180 mg/m2) 和 pelareorep (1 × 1010 TCID50–3 × 1010 TCID50)] 的剂量递增试验在奥沙利铂难治/不耐受、KRAS 突变的 mCRC 成人患者中实施。每 4 周，在第 1-5 天，在 1 小时内静脉注射 Pelareorep。其他研究包括药代动力学、肿瘤形态和免疫反应。在 FOLFIRI 初治患者中，最高剂量的 FOLFIRI/贝伐珠单抗（180 mg/m2 伊立替康）和 pelareorep（3 × 1010 TCID50）耐受性良好，没有剂量限制性毒性。在推荐的 II 期剂量下，6 名患者中有 3 名 (50%) 有部分反应；中位无进展生存期和总生存期（PFS、OS）分别为 65.6 周和 25.1 个月。毒性包括骨髓抑制、疲劳和腹泻。透射电子显微镜显示处于不同发育阶段的病毒工厂（形成囊泡结构的病毒集合）。针对病毒衣壳 σ-1 蛋白的免疫金染色表明病毒在肿瘤细胞中“归巢”。细胞核显示出足够的常染色质区域，表明转录活跃。流式细胞术显示树突状细胞快速成熟（48 小时），随后激活细胞毒性 T 细胞（7 天）。pelareorep 与 FOLFIRI/贝伐单抗的组合是安全的。PFS 和 OS 数据令人鼓舞，值得进一步探索。