Immune mechanisms and molecular therapeutic strategies to enhance immunotherapy in non-muscle invasive bladder cancer: Invited review for special issue "Seminar: Treatment Advances and Molecular Biology Insights in Urothelial Carcinoma"

Abstract

Intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) has been the standard of care for patients with high-risk non non-muscle invasive bladder cancer (NMIBC) for over four decades. Despite its success as a cancer immunotherapy, disease recurrence and progression remain common. Current efforts are focused on developing effective and well-tolerated alternatives to BCG and salvage bladder preservation therapies after BCG has failed. The focus of this review is to synthesize our current understanding of the molecular biology and tumor immune microenvironment of NMIBC to provide rationale for existing and emerging therapeutic targets. We highlight recent and ongoing clinical trials and define the current treatment landscape, challenges, and future directions of salvage treatment. Combination regimens that are rationally designed will be needed to make meaningful therapeutic advancements. Investigations into the molecular underpinnings of NMIBC are leading to the emergence of predictive molecular biomarkers that provide greater insight into the clinical heterogeneity of NMIBC and enable us to identify drivers of treatment resistance and new therapeutic targets.

Keywords: BCG; Bacillus Calmette-Guérin; Bladder urothelial carcinoma; Immunotherapy; NMIBC; Non–muscle invasive bladder cancer.

Figure 1.

Therapeutic Strategies to Modulate the Tumor Immune Microenvironment in NMIBC. TME: tumor microenvironment; BCG: Bacillus Calmette-Guérin, TMB: tumor mutational burden; FGFR3: fibroblast growth factor 3; IL: interleukin; IFN: interferon, IDO: Indoleamine-dioxygenase; IFN, interferon, TGF, transforming growth factor; NK natural killer; PD-1/PD-L1: Programmed cell death-ligand 1; MDSC, Myeloid-derived suppressor cells; VEGF, Vascular endothelial growth factor