BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets

Abstract

Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90-95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette-Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.

Keywords: Bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer; bladder sparing treatment; chemo-hyperthermia; gene therapy; immunotherapy; non-muscle-invasive bladder cancer; photodynamic therapy.

Figure 1

Active molecules and mechanism of action of intravesical chemotherapy. The image was created with BioRender.com.

Figure 2

Scheme and mechanism of chemo—hyperthermia treatment. The image was created with BioRender.com.

Figure 3

Schematic summary of immunotherapeutic approaches for patients with upper non-muscle-invasive bladder carcinoma (NMIBC) unresponsive to treatment with Bacillus Calmette–Guerin (BCG). Abbreviations are as follows: EpCAM: epithelial cell adhesion molecule; IFN: interferon; IL: interleukin; MCNA: mycobacterium phlei cell wall-nucleic acid complex; NAI: nogapendekin alfa inbakicept; NK cell: natural kill cell; PD-1: programmed cell death protein 1; PD-L1/2: programmed cell death protein ligand 1; TNF: tumor necrosis factor. The image was created with BioRender.com.

Figure 4

Schematic summary of the gene therapies for patients with non-muscle-invasive bladder carcinoma (NMIBC) unresponsive to Bacillus Calmette–Guerin (BCG) treatment. Abbreviations are as follows: dtA: diphtheria toxin; IFN: interferon; jetPEI™: polyethyleneimine; rAd-IFNα/Syn3: Nadofaragene firadenovec. The image was created with BioRender.com.

Figure 5

Working principle of photodynamic therapy (PDT). Abbreviations are as follows: PS0: ground state photosensitizer; PS1: excited photosensitizer. The image was created with BioRender.com.