Oncolytic Viruses for the Treatment of Bladder Cancer: Advances, Challenges, and Prospects

Abstract

Bladder cancer is one of the most prevalent cancers. Despite recent advancements in bladder cancer therapy, new strategies are still required for improving patient outcomes, particularly for those who experienced Bacille Calmette-Guerin failure and those with locally advanced or metastatic bladder cancer. Oncolytic viruses are either naturally occurring or purposefully engineered viruses that have the ability to selectively infect and lyse tumor cells while avoiding harming healthy cells. In light of this, oncolytic viruses serve as a novel and promising immunotherapeutic strategy for bladder cancer. A wide diversity of viruses, including adenoviruses, herpes simplex virus, coxsackievirus, Newcastle disease virus, vesicular stomatitis virus, alphavirus, and vaccinia virus, have been studied in many preclinical and clinical studies for their potential as oncolytic agents for bladder cancer. This review aims to provide an overview of the advances in oncolytic viruses for the treatment of bladder cancer and highlights the challenges and research directions for the future.

Keywords: bladder cancer; immunotherapy; oncolytic viral therapy; oncolytic virus.

Figure 1

Proposed antitumor mechanisms of oncolytic viruses in bladder cancer. The oncolytic viruses (OVs) can be administered intravenously, intravesically, and intratumorally. OVs selectively infect bladder cancer cells while avoiding harming healthy cells. After the infection, OVs replicate in bladder cancer cells and finally lyse the malignant cells. The infection and direct oncolysis result in the release of cell-derived damage-associated molecular patterns (DAMPs), viral pathogen-associated molecular patterns (PAMPs), soluble tumor-associated antigens (TAAs), and various cytokines. These molecules recruit and activate antigen-presenting cells such as dendritic cells (DCs), natural killer (NK) cells, and other immune cells to the infection site. DCs take up soluble tumor antigens and then activate adaptive T cell responses against the tumor at regional lymph nodes. NK cells and cytotoxic T lymphocytes can recognize and kill tumor cells. Finally, OVs break down the immune suppressive tumor microenvironment that consists of immunosuppressive cells and a dense stroma to establish an immunologically “hot” tumor microenvironment. This remodeling promotes the immune system to recognize and kill primary, metastatic, or recurrent malignant cells. In addition, many OVs can effectively suppress intratumor angiogenesis and reduce the supply of nutrients and oxygen to the tumor by direct lysing the vascular endothelial cells, instigating the formation of microthrombosis, and expressing anti-angiogenesis viral proteins.