Immunotherapy Strategy Targeting Programmed Cell Death Ligand 1 and CD73 with Macrophage-Derived Mimetic Nanovesicles to Treat Bladder Cancer

Author(s):  
Qidong Zhou ◽  
Weihong Ding ◽  
Zhiyu Qian ◽  
Quangang Zhu ◽  
Chuanyu Sun ◽  
...  
2021 ◽  
Author(s):  
Qidong Zhou ◽  
Weihong Ding ◽  
Zhiyu Qian ◽  
Quangang Zhu ◽  
Chuanyu Sun ◽  
...  

Abstract BackgroundThe tumor microenvironment in bladder cancer exerts an inhibitory effect on immune effector cells. Thus, removing this inhibitory effect could help improve the efficacy of immune checkpoint inhibitors, and combination immunotherapy is a promising strategy for increasing the proportion of patients with bladder cancer who benefit from immune checkpoint inhibitors. However, it is difficult to effectively and simultaneously deliver multiple drugs to the tumor tissue. In this study, we describe the design and in vivo validation of macrophage-derived exosome-mimetic nanovesicles (EMVs) as a nanoplatform for coloading and targeted delivery of a CD73 inhibitor (AB680) and monoclonal antibodies targeting programmed cell death ligand 1 (aPDL1). ResultsOur results indicated that these nanocomplexes (AB680@EMVs-aPDL1) were highly stable, provided adequate biosafety in vivo, and exhibited enhanced targeting in a mouse model of bladder cancer. Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted activation of cytotoxic T lymphocytes, resulting in suppression of tumor growth in vivo. ConclusionsTherefore, using EMVs to deliver a combination of aPDL1 and a CD73 inhibitor may be an effective combined immunotherapy strategy for treating bladder cancer.


Author(s):  
Jun Hyeok Heo ◽  
Ki Chung Park ◽  
Kang Su Cho ◽  
Sung Joon Hong ◽  
Kyung Seok Han

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1181 ◽  
Author(s):  
Mikołaj Wołącewicz ◽  
Rafał Hrynkiewicz ◽  
Ewelina Grywalska ◽  
Tomasz Suchojad ◽  
Tomasz Leksowski ◽  
...  

Bladder cancer is one of the most significant genitourinary cancer, causing high morbidity and mortality in a great number of patients. Over the years, various treatment methods for this type of cancer have been developed. The most common is the highly efficient method using Bacillus Calmette-Guerin, giving a successful effect in a high percentage of patients. However, due to the genetic instability of bladder cancer, together with individual needs of patients, the search for different therapy methods is ongoing. Immune checkpoints are cell surface molecules influencing the immune response and decreasing the strength of the immune response. Among those checkpoints, the PD-1 (programmed cell death protein-1)/PD-L1 (programmed cell death protein ligand 1) inhibitors aim at blocking those molecules, which results in T cell activation, and in bladder cancer the use of Atezolizumab, Avelumab, Durvalumab, Nivolumab, and Pembrolizumab has been described. The inhibition of another pivotal immune checkpoint, CTLA-4 (cytotoxic T cell antigen), may result in the mobilization of the immune system against bladder cancer and, among anti-CTLA-4 antibodies, the use of Ipilimumab and Tremelimumab has been discussed. Moreover, several different approaches to successful bladder cancer treatment exists, such as the use of ganciclovir and mTOR (mammalian target of rapamycin) kinase inhibitors, IL-12 (interleukin-12) and COX-2 (cyclooxygenase-2). The use of gene therapies and the disruption of different signaling pathways are currently being investigated. Research suggests that the combination of several methods increases treatment efficiency and the positive outcome in individual.


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