New Perspectives in the Medical Treatment of Non-Muscle-Invasive Bladder Cancer: Immune Checkpoint Inhibitors and Beyond

Abstract

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette-Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results.

Keywords: BGC-unresponsive; immune-checkpoint inhibitors; immunotherapy; non-muscle-invasive bladder cancer; pembrolizumab.

Figure 1

BCG instillation elicits both innate and adaptative immune response against urothelial cancer cells. BCG, Bacillus Calmette–Guérin; DC, Dendritic Cell; IL, Interleukin; CXCL10, C-X-C motif Chemokine Ligand 10; GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; CCL2, C-C Motif Chemokine Ligand 2; CCL3, C-C Motif Chemokine Ligand 3; PML, Polymorphonuclear Leukocytes; Th, Helper T cell; Treg, Regulatory T cell; Mϕ, Macrophage; CD8, Cluster of Differentiation 8; NK, Natural Killer; ROS, Reactive Oxygen Species; IFN-γ, Interferon-γ; TNF, Tumour Necrosis Factor.

Figure 2

Main targets of novel drugs being investigated in BCG-unresponsive NMIBC. TPH, Tryptophan; KYN, Kynurenine; IFNα2b, Interferon α2b; DC, Dendritic Cell; PD1, Programmed cell Death protein 1; PD-L1, Programmed Death-Ligand 1; mAb, monoclonal Antibody; GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; FGFR, Fibroblast Growth Factor Receptor; TKI, Tyrosine Kinase Inhibitors; IDO1, Indoleamine 2,3-Dioxygenase 1; IL-15Rα, Interleukin-15 receptor α; MHCII, Major Histocompatibility Complex Class II; TCR, T Cell Receptor; TLR7, Toll-like Receptor 7; EpCAM, Epithelial Cell Adhesion Molecule; CD3, Cluster of Differentiation 3.