Emerging treatments for bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer

Abstract

Intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immunotherapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies ‘BCG-unresponsiveness’. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.

Tumor-Associated Mast Cells in Urothelial Bladder Cancer: Optimizing Immuno-Oncology

“…As previously mentioned, NMIBC are characterized by frequent recurrence and progression to muscle invasive bladder cancer (MIBC) [ 1 , 2 , 3 , 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 72 ]. Transurethral resection of bladder tumors, followed by intravesical Bacillus Calmette–Guérin (BCG) instillation, is the current gold standard for treating patients with intermediate- and high-risk NMIBC [ 1 , 2 , 3 , 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. The BCG vaccine, comprising live attenuated Mycobacterium bovis, binds to fibronectin in the urothelium and causes a direct tumor and immunological response [ 72 , 79 ].…”

“…Transurethral resection of bladder tumors, followed by intravesical Bacillus Calmette–Guérin (BCG) instillation, is the current gold standard for treating patients with intermediate- and high-risk NMIBC [ 1 , 2 , 3 , 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. The BCG vaccine, comprising live attenuated Mycobacterium bovis, binds to fibronectin in the urothelium and causes a direct tumor and immunological response [ 72 , 79 ]. It has been utilized as immunotherapeutic agent for NMIBC for over 40 years; however, the mechanism underlying a BCG-mediated anti-tumor response is not clearly elucidated [ 72 , 75 ].…”

“…The BCG vaccine, comprising live attenuated Mycobacterium bovis, binds to fibronectin in the urothelium and causes a direct tumor and immunological response [ 72 , 79 ]. It has been utilized as immunotherapeutic agent for NMIBC for over 40 years; however, the mechanism underlying a BCG-mediated anti-tumor response is not clearly elucidated [ 72 , 75 ]. Nevertheless, this mechanism is likely a complex interaction between the innate and adaptive immune system [ 26 , 27 , 75 , 80 ].…”

Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment

“…Patients with non-muscle invasive urothelial bladder cancer (NMI-UBC, carcinoma in situ, Ta, or T1), which accounts for approximately 75% of initial UBC diagnoses, demonstrate unexpectedly high recurrence rate and multifocality with disease progression to muscle-invasive UBC (MI-UBC), which has a much less favorable prognosis and occurs in 10-15% of patients diagnosed with NMI-UBC [1][2][3][4][5][6]. For patients who present with non-metastatic MI-UBC, consensus guidelines recommend radical cystectomy and urinary diversion combined with lymph node dissection following cisplatin-based neoadjuvant chemotherapy.…”

“…Although approximately 50-70% of locally advanced or metastatic UBCs (a/m UBCs) patients respond to chemotherapy, unfortunately, in most cases, progression or recurrence occurs with conventional strategies, and limited benefit is seen in second-line and later setting [2][3][4][5]. The prognosis of patients affected by locally advanced or metastatic (a/m) UBC remains dismal, with a 5-year overall survival (OS) of approximately 10-15% [1][2][3][4][5][6].…”