DataSheet_1_Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model.pdf

IntroductionMalignant mesothelioma is a rare and aggressive form of cancer. Despite improvements in cancer treatment, there are still no curative treatment modalities for advanced stage of the malignancy. The aim of this study was to evaluate the anti-tumor efficacy of a novel combinatorial therapy combining AdV5/3-D24-ICOSL-CD40L, an oncolytic vector, with an anti-PD-1 monoclonal antibody.
MethodsThe efficacy of the vector was confirmed in vitro in three mesothelioma cell lines – H226, Mero-82, and MSTO-211H, and subsequently the antineoplastic properties in combination with anti-PD-1 was evaluated in xenograft H226 mesothelioma BALB/c and humanized NSG mouse models.
Results and discussionAnticancer efficacy was attributed to reduced tumour volume and increased infiltration of tumour infiltrating lymphocytes, including activated cytotoxic T-cells (GrB+CD8+). Additionally, a correlation between tumour volume and activated CD8+ tumour infiltrating lymphocytes was observed. These findings were confirmed by transcriptomic analysis carried out on resected human tumour tissue, which also revealed upregulation of CD83 and CRTAM, as well as several chemokines (CXCL3, CXCL9, CXCL11) in the tumour microenvironment. Furthermore, according to observations, the combinatorial therapy had the strongest effect on reducing mesothelin and MUC16 levels. Gene set enrichment analysis suggested that the combinatorial therapy induced changes to the expression of genes belonging to the “adaptive immune response” gene ontology category. Combinatorial therapy with oncolytic adenovirus with checkpoint inhibitors may improve anticancer efficacy and survival by targeted cancer cell destruction and triggering of immunogenic cell death. Obtained results support further assessment of the AdV5/3-D24-ICOSL-CD40L in combination with checkpoint inhibitors as a novel therapeutic perspective for mesothelioma treatment.

【引言】恶性胸膜间皮瘤（malignant mesothelioma）是一种罕见且高侵袭性的恶性肿瘤。尽管癌症治疗手段已取得进展，但针对该恶性肿瘤的晚期阶段，目前仍无治愈性治疗方案。本研究旨在评估一种新型联合疗法的抗肿瘤疗效，该疗法将溶瘤载体（oncolytic vector）AdV5/3-D24-ICOSL-CD40L与抗PD-1单克隆抗体（anti-PD-1 monoclonal antibody）相结合。
【方法】该载体的抗肿瘤活性已在3种间皮瘤细胞系（H226、Mero-82及MSTO-211H）中通过体外实验得到验证；随后，本研究在H226间皮瘤异种移植（xenograft）BALB/c小鼠及人源化NSG小鼠（humanized NSG mouse）模型中，评估了该载体与抗PD-1联合疗法的抗肿瘤特性。
【结果与讨论】抗癌疗效体现在肿瘤体积缩小以及肿瘤浸润淋巴细胞（tumour infiltrating lymphocytes）浸润程度的提升，其中包括活化的细胞毒性T细胞（activated cytotoxic T-cells，GrB+CD8+）。此外，本研究还观察到肿瘤体积与活化CD8+肿瘤浸润淋巴细胞之间存在相关性。对切除的人类肿瘤组织进行的转录组学分析（transcriptomic analysis）验证了上述发现，该分析同时揭示了肿瘤微环境（tumour microenvironment）中CD83、CRTAM以及多种趋化因子（CXCL3、CXCL9、CXCL11）的表达上调。进一步观察表明，该联合疗法对降低间皮素（mesothelin）与MUC16水平的效果最为显著。基因集富集分析（gene set enrichment analysis）显示，该联合疗法可诱导属于“适应性免疫应答（adaptive immune response）”基因本体（gene ontology）类别的基因表达发生改变。溶瘤腺病毒（oncolytic adenovirus）联合免疫检查点抑制剂（checkpoint inhibitors）的疗法，可通过靶向杀伤癌细胞并触发免疫原性细胞死亡（immunogenic cell death），提升抗癌疗效并延长患者生存期。本研究所得结果支持将AdV5/3-D24-ICOSL-CD40L与免疫检查点抑制剂联合疗法作为间皮瘤治疗的新型治疗方案，有待进一步评估。