Immunotherapy of High Risk Non-Muscle Invasive Bladder Cancer

ABSTRACT

Introduction: Bladder cancer remains a prevalent and often lethal cancer. Fortunately, recent clinical trials using immunotherapeutics demonstrate promise to improve treatment outcomes. Several of these immunotherapies have already established their value in the metastatic space and likely will soon have indications in the non-metastatic space.

Areas covered: This review will cover immunotherapies ranging for well-studied BCG administration to more novel medications such as PD-L1/PD-1 inhibitors, CTLA-4 inhibitors, IL-15 super agonists, and immune modulating gene therapies. Specifically, this article will address the mechanisms of actions, clinical evidence supporting their use, and the presence of any FDA regulatory approval for these medications in the treatment of high-risk non-muscle invasive bladder cancer.

Expert opinion: With the publication of clinical data supporting the use of immunotherapies, these novel medications are likely to be adopted for treatment of high-grade non-metastatic bladder cancer. While BCG is likely to remain a primary medication for high-grade bladder cancer for the near future, BCG will likely be co-administered with immunomodulatory medications in some patients to enhance the medications effect in the future. Clinical trials are still ongoing and will demonstrate which of these multiple treatment options yield results worthy of a modification in our current treatment paradigm.

KEYWORDS:

• Bladder cancer
• immunotherapy
• PD-L1 inhibitors
• CTLA-4 inhibitors
• IL-15 agonists
• gene therapy
• nadofaragene firadenovec
• pembrolizumab
• atezolizumab
• N-803
• Ipilimumab

Article highlights

• Multiple immunotherapeutic medications are currently being evaluated for the treatment of non-muscle invasive high-grade bladder cancer. This article discusses these medications, their mechanisms, and early clinical data.

• Despite decades of research BCG remains the primary treatment for high-grade non-muscle invasive bladder cancer

• Early trials using PD-L1/PD-1 inhibitors to prevent immune system attenuation have shown early promise to treat bladder cancer in the near term and have recently received FDA approval for treatment of muscle-invasive disease in specific clinical settings.

• IL-15 super agonists have shown strong early clinical evidence for the treatment of BCG naïve and BCG refractory patients, but the duration of follow up has not been adequate to completely assess the effect of these medications.

• Recently, gene therapy using a non-replicating recombinant adenovirus vector which delivers a copy of a human interferon alfa-2b (IFNA2) gene and a polyamide surfactant, was tested for the treatment of BCG refractory disease with promising 30% 12-month complete response rates. Longer follow up is needed.

Declaration of interest

D Theodorescu is on the scientific advisory board for Urogen.

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded