A recombinant Newcastle Disease Virus (NDV), encoding either a human (NDVhuGM-CSF, MEDI5395) or murine (NDVmuGM-CSF) GM-CSF transgene, combined broad oncolytic activity with the ability to significantly modulate genes related to immune functionality in human tumor cells. Replication in murine tumor lines was significantly diminished relative to human tumor cells. Nonetheless, intratumoral injection of NDVmuGM-CSF conferred antitumor effects in three syngeneic models in vivo ; with efficacy further augmented by concomitant treatment with anti–PD-1/PD-L1 or T-cell agonists. Ex vivo immune profiling, including T-cell receptor sequencing, revealed profound immune-contexture changes consistent with priming and potentiation of adaptive immunity and tumor microenvironment (TME) reprogramming toward an immune-permissive state. CRISPR modifications rendered CT26 tumors significantly more permissive to NDV replication, and in this setting, NDVmuGM-CSF confers immune-mediated effects in the noninjected tumor in vivo . Taken together, the data support the thesis that MEDI5395 primes and augments cell-mediated antitumor immunity and has significant utility as a combination partner with other immunomodulatory cancer treatments.

中文翻译：

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重组新城疫病毒免疫疗法可促进溶瘤作用和持久的全身抗肿瘤免疫

重组新城疫病毒 (NDV)，编码人（NDVhuGM-CSF，MEDI5395）或鼠（NDVmuGM-CSF）GM-CSF 转基因，结合广泛的溶瘤活性和显着调节与人类肿瘤免疫功能相关的基因的能力细胞。相对于人类肿瘤细胞，小鼠肿瘤细胞系中的复制显着减少。尽管如此，肿瘤内注射 NDVmuGM-CSF 在体内三种同源模型中均具有抗肿瘤作用；与抗 PD-1/PD-L1 或 T 细胞激动剂联合治疗可进一步增强疗效。离体免疫分析，包括 T 细胞受体测序，揭示了与适应性免疫和肿瘤微环境 (TME) 重新编程为免疫允许状态的启动和增强相一致的深刻免疫环境变化。CRISPR 修饰使 CT26 肿瘤明显更容易接受 NDV 复制，在这种情况下，NDVmuGM-CSF 在体内对未注射的肿瘤产生免疫介导的作用。综上所述，这些数据支持 MEDI5395 启动和增强细胞介导的抗肿瘤免疫力并且作为与其他免疫调节癌症治疗的组合伙伴具有重要效用的论点。