Immunotherapy for urothelial cancer: from BCG to checkpoint inhibitors and beyond

Abstract

Since its introduction almost 40 years ago, intravesical BCG for non-muscle invasive bladder cancer remains one of the most successful cancer immunotherapies. However, up to 40% of patients will progress after BCG therapy and develop invasive bladder cancer. Despite its extensive clinical use, we are only beginning to understand how BCG works. Here we review preclinical and clinical data that implicate BCG-induced Th1 and cytotoxic cellular immune responses in cancer regression. We propose that future immunotherapies should aim to augment Th1 and/or cellular responses in those that fail BCG therapy. We review clinical trials of immunotherapy in bladder cancer with a focus on the promising role of checkpoint blockade inhibitors that target the programmed cell death 1/programmed death-ligand 1 (PD-L1) axis and/or cytotoxic T lymphocyte antigen 4.

Keywords:

• CTLA-4
• immune checkpoint
• immunoediting
• immunosurveillance
• PD-1
• PD-L1
• Th1

Financial & competing interests disclosure

The authors have no 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.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Bladder cancer is a common cancer, and the outcome for metastatic disease remains dismal.

• Adjuvant intravesical BCG remains the standard of care in non-muscle-invasive bladder cancer with favorable response rates compared to intravesical chemotherapy, albeit at increased toxicity.

• Up to 40% of non-muscle-invasive bladder cancers will recur after intravesical BCG with progression to muscle-invasive disease requiring cystectomy or metastatic disease.

• The mechanism of BCG action is not fully understood but clearly involves a BCG-induced immune response, particularly a Th1 and cytotoxic response.

• Failure to mount a Th1 or cytotoxic response after intravesical BCG results in treatment failure and disease progression.

• Preclinical trials in mouse models have shown benefit of either exogenous Th1 cytokines or immune checkpoint blockade in mice that fail intravesical BCG therapy.

• Immune checkpoint inhibition with antibodies targeting the programmed cell death 1/PD-L1 axis has shown promising activity and is being developed further in current clinical trials.

• Biomarkers for response to checkpoint blockade are urgently needed to identify those most likely to respond to treatment and minimize the significant toxicities associated with these immunotherapies.