肿瘤细胞治疗研究
英文原题：Enhanced potency of immune checkpoint inhibitors against poorly immunological solid tumors by immune stimulatory oncolytic adenoviruses-mediated remodeling of the tumor microenvironment.
Enhanced potency of immune checkpoint inhibitors against poorly immunological solid tumors by immune stimulatory oncolytic adenoviruses-mediated remodeling of the tumor microenvironment.
免疫检查点抑制剂（ICI）在多项临床试验中针对多种实体瘤显示出令人鼓舞的疗效。
免疫检查点抑制剂（ICI）在多项临床试验中对多种实体瘤显示出令人鼓舞的疗效。然而，对于具有高水平免疫抑制和低水平TIL（肿瘤浸润淋巴细胞）的非免疫原性肿瘤患者，ICI单药治疗往往无效。为解决这些局限性，我们研究了ICI［抗PD-1抗体（αPD-1）、抗PD-L1抗体（αPD-L1）或抗CTLA-4抗体（αCTLA-4）］与几种不同的免疫刺激性溶瘤腺病毒（Ads）的联合方案，这些溶瘤腺病毒表达不同的抗肿瘤细胞因子或免疫调节因子的组合［例如，（1）白细胞介素（IL）-12和粒细胞-巨噬细胞集落刺激因子（GM-CSF；RdB/IL12/GMCSF），（2）IL-12和靶向血管内皮生长因子的短发夹核糖核酸（shRNA）（RdB/IL12/shVEGF），（3）IL-12和核心蛋白聚糖（RdB/IL12/DCN），（4）GM-CSF和胸苷激酶（RdB/IL12/GMCSF-TK），或（5）IL-12、GM-CSF和松弛素（RdB/IL12/GMCSF-RLX）］，以克服肿瘤诱导的免疫抑制。通过对联合治疗方案进行比较评估，我们的研究结果确定αPD-1是最佳的ICI候选者，可与不同的溶瘤Ads协同作用，针对免疫原性较差的实体瘤诱导强效的抗肿瘤免疫应答。
Immune checkpoint inhibitor (ICI) have shown promising results against a variety of solid tumors across clinical trials. However, ICI monotherapy is often ineffective in patients with non-immunogenic tumors that exhibit high level of immunosuppression and low level of tumor infiltrating lymphocytes. To address these limitations, we have investigated a combination of ICIs [anti-PD-1 antibody (αPD-1), anti-PD-L1 antibody (αPD-L1), or anti-CTLA-4 antibody (αCTLA-4)] with several different immune stimulatory oncolytic adenoviruses (Ads) expressing different combinations of antitumor cytokines or immune modulatory factors [e.g., (1) interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF; RdB/IL12/GMCSF), (2) IL-12 and short hairpin ribonucleic acid (shRNA) targeting vascular endothelial growth factor (RdB/IL12/shVEGF), (3) IL-12 and decorin (RdB/IL12/DCN), (4) GM-CSF, and thymidine kinase (RdB/IL12/GMCSF-TK), or (5) IL-12, GM-CSF, and relaxin (RdB/IL12/GMCSF-RLX)] to overcome tumor-induced immunosuppression. Through comparative evaluation of combination therapy regimens, our findings have identified αPD-1 as the optimal ICI candidate to synergize with different oncolytic Ads to induce potent antitumor immune response against poorly immunological solid tumors.
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