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Review
. 2023 Aug 9;24(16):12596.
doi: 10.3390/ijms241612596.

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

Francesco Claps  1   2 , Nicola Pavan  3 , Luca Ongaro  1 , Domenico Tierno  4 , Gabriele Grassi  5 , Carlo Trombetta  1 , Gabriele Tulone  3 , Alchiede Simonato  3 , Riccardo Bartoletti  6 , Laura S Mertens  2 , Bas W G van Rhijn  2 , Maria Carmen Mir  7 , Bruna Scaggiante  4
Affiliations
Review

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

Francesco Claps et al. Int J Mol Sci. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Active molecules and mechanism of action of intravesical chemotherapy. The image was created with BioRender.com.
Figure 2
Figure 2
Scheme and mechanism of chemo—hyperthermia treatment. The image was created with BioRender.com.
Figure 3
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
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
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.
See this image and copyright information in PMC

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