The current status of gene therapy in bladder cancer

ABSTRACT

Introduction

Gene therapy aims to alter the biological properties of cells through the therapeutic delivery of nucleotides to treat a disease. Although originally developed to treat genetic disorders, the majority of gene therapy development today is for the treatment of cancer, including bladder cancer.

Areas covered

Following a brief history and a discussion of the mechanisms of gene therapy, we will focus on the current and future gene therapy strategies for bladder cancer. We will review the most consequential clinical trials published in the field.

Expert opinion

Recent transformative breakthroughs in bladder cancer research have deeply characterized the major epigenetic and genetic alterations of bladder cancer and have radically transformed our view of tumor biology and generated new hypotheses for therapy. These advances provided the opportunity to begin to optimize strategies for effective gene therapy for bladder cancer. Clinical trials have shown promising results, especially in BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC), where effective second-line therapy remains an unmet need for patients facing cystectomy. Efforts are underway to develop effective combination strategies targeting resistance mechanisms to gene therapy for NMIBC.

KEYWORDS:

• Bladder cancer
• clinical trials
• gene therapy
• genetic vectors
• molecular genetics
• viral vectors

Article highlights

• Viral vectors are the most frequently used vectors for gene therapy clinical trials.

• Over the last two decades, trials’ focus switched from genetic disorders to cancer.

• The bladder is particularly suited for topical gene therapy as it is a cavity which allows direct exposure of the tumor and urothelium to the vector carrying the therapeutic gene following intravesical administration. Improved understanding of the genomic events characterizing bladder cancers led to the development of a multitude of therapeutics targeting a variety of genes.

• Optimization of gene transfection is possible through disruption of the glycosaminoglycan urothelial layer, increasing specific cell-surface viral receptors or by delivering replication competent viral vector.

• Most clinical trials in bladder cancer focused on BCG-unresponsive non-muscle-invasive bladder cancer and showed promising results.

• Future studies will investigate the role for intravesical gene therapy for other disease states either as a monotherapy or as part of a combination approach.

Declaration of interest

C Dinney reports compensation for Scientific/Advisory Committee Member for AstraZeneca Pharmaceuticals, UroGen Pharma (formerly Theracoat Ltd.); consulting fees from STIMIT Corporation; board member position for DF/HCC Kidney Cancer SPORE Advisory Board; research funding from Cancer Prevention Research Institute of Texas (CPRIT), Department of Defense (DoD), and NIH/NCI.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.