PDF(Pubmed)
Abstract：
Bladder cancer is a common type of cancer around the world, and the majority of patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Although low-risk NMIBC has a good prognosis, the disease recurrence rate and development of treatment-refractory disease remain high in intermediate- to high-risk NMIBC patients. To address these challenges for the treatment of NMIBC, a novel combination therapy composed of an oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and relaxin (RLX; HY-oAd) and a clinical-stage glycogen synthase kinase (GSK)-3β inhibitor (9-ING-41; elraglusib) was investigated in the present report. Our findings demonstrate that HY-oAd and 9-ING-41 combination therapy (HY-oAd+9-ING-41) exerted superior inhibition of tumor growth compared with respective monotherapy in a syngeneic NMIBC tumor model. HY-oAd+9-ING-41 induced high-level tumor extracellular matrix (ECM) degradation and a more potent antitumor immune response than the respective monotherapy. In detail, HY-oAd+9-ING-41 induced superior accumulation of intratumoral T cells, prevention of immune cell exhaustion, and induction of tumor-specific adaptive immune response compared to either monotherapy. Collectively, these results demonstrate that the combination of HY-oAd and 9-ING-41 may be a promising approach to elicit a potent antitumor immune response against bladder cancer.
摘要：
膀胱癌是世界上常见的一种癌症，大多数患者被诊断为非肌肉浸润性膀胱癌（NMIBC）。尽管低风险NMIBC具有良好的预后，在中高危NMIBC患者中,疾病复发率和难治性疾病的发展仍然很高.为了应对NMIBC治疗的这些挑战，一种由共表达白细胞介素（IL）-12，粒细胞-巨噬细胞集落刺激因子（GM-CSF）的溶瘤腺病毒（oAd）组成的新型联合疗法，本报告研究了松弛素（RLX；HY-oAd）和临床阶段糖原合酶激酶（GSK）-3β抑制剂（9-ING-41；elraglusib）。我们的发现表明，在同基因NMIBC肿瘤模型中，与各自的单一疗法相比，HY-oAd和9-ING-41联合疗法（HY-oAd9-ING-41）对肿瘤生长具有更好的抑制作用。与各自的单一疗法相比，HY-oAd9-ING-41诱导了高水平的肿瘤细胞外基质（ECM）降解和更有效的抗肿瘤免疫反应。详细来说,HY-oAd+9-ING-41诱导肿瘤内T细胞的优良积累，预防免疫细胞耗尽，与任一单一疗法相比，诱导肿瘤特异性适应性免疫反应。总的来说，这些结果表明,HY-oAd和9-ING-41的组合可能是引发针对膀胱癌的有效抗肿瘤免疫应答的有希望的方法.
