肿瘤细胞治疗研究
英文原题：Oncolytic adenovirus in combination with PD-L1-targeted radioimmunotherapy exerts synergistic antitumor effect against pancreatic cancer.
我们的研究结果表明，HY-oAd能以多方面的方式增强177 Lu-aPD-L1在肿瘤内的积聚，从而激发针对促结缔组织增生性和免疫原性差的胰腺肿瘤的协同抗肿瘤免疫反应。
迄今为止，尚无任何放射免疫治疗（RIT）方案获得美国食品药品监督管理局批准用于治疗胰腺癌。胰腺癌的高度促结缔组织增生和免疫荒漠表型仍是两大主要障碍，削弱了常规治疗（放疗和化疗）和免疫治疗（免疫检查点抑制剂和CAR-T 细胞）的疗效。
为克服这些障碍，研究了一种共表达白细胞介素-12、粒细胞-巨噬细胞集落刺激因子和松弛素的溶瘤腺病毒（oAd）（HY-oAd），并将其与靶向程序性死亡配体1（PD-L1）的RIT（镥-177标记的阿替利珠单抗（177Lu-aPD-L1））联合使用。
HY-oAd 治疗可提高 PD-L1 表达水平并促进胰腺肿瘤细胞外基质降解，从而导致 aPD-L1 或 64 Cu-aPD-L1 在肿瘤组织中的蓄积增加。HY-oAd 与 aPD-L1 或 177 Lu-aPD-L1 联合使用（分别为 HY-oAd+aPD-L1 或 HY-oAd+ 177 Lu-aPD-L1）在皮下和原位胰腺肿瘤模型中均比各自的单药治疗引发更强的抗肿瘤效果。HY-oAd+aPD-L1 联合治疗的强效抗肿瘤效果归因于相比各自的单药治疗，树突状细胞和 CD4 + 或 CD8 + T 细胞在肿瘤内的浸润和活化更优。
BACKGROUND: To date, no radioimmunotherapy (RIT) regimen has been approved by US Food and Drug Administration for the treatment of pancreatic cancers. Highly desmoplastic and immune-desert phenotypes of pancreatic cancer remain two major hurdles that attenuate the efficacy of conventional treatment (radiotherapy and chemotherapy) and immunotherapeutic (immune checkpoint inhibitors and chimeric antigen receptor T cells). METHOD: To overcome these hurdles, an oncolytic adenovirus (oAd) co-expressing interleukin-12, granulocyte macrophage colony-stimulating factor, and relaxin (HY-oAd) was investigated in combination with programmed death-ligand 1 (PD-L1)-targeted RIT (lutetium-177-labeled atezolizumab ( 177 Lu-aPD-L1)). RESULTS: HY-oAd treatment was shown to elevate PD-L1 expression level and promoted degradation of extracellular matrix of pancreatic tumors, resulting in increased aPD-L1 or 64 Cu-aPD-L1 accumulation in tumor tissues. HY-oAd in combination with either aPD-L1 or 177 Lu-aPD-L1 (HY-oAd+aPD-L1 or HY-oAd+ 177 Lu-aPD-L1, respectively) elicited more potent antitumor effect against the pancreatic tumors than respective monotherapy in both subcutaneous and orthotopic pancreatic tumor models. The potent antitumor effect of HY-oAd+aPD-L1 combination therapy was due to superior intratumoral infiltration and activation of dendritic cells and CD4 + or CD8 + T cells over the respective monotherapy. CONCLUSION: Collectively, our findings demonstrate that HY-oAd can enhance intratumoral accumulation of 177 Lu-aPD-L1 in a multifaceted manner to elicit synergistic antitumor immune response against desmoplastic and poorly immunogenic pancreatic tumors.
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