Checkpoint inhibitors: the new treatment paradigm for urothelial bladder cancer

Abstract

Bladder cancer is the most common malignancy involving the genitourinary system (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). In the USA, it is the fifth most common cancer and approximately 79,000 new cases will be diagnosed in 2017 (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). The mortality from bladder cancer is approximately 17,000 deaths each year (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). The incidence rate for bladder cancer is higher in men compared to women. Risk factors are predominantly related to tobacco smoking, although infection with Schistosoma haematobium is another risk factor in selected populations (Antoni et al. in Eur Urol, 71:96-108, 2017). Cisplatin-based systemic chemotherapy regimens remain the standard of care in both the neoadjuvant and metastatic setting for muscle-invasive bladder cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602-4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012; Bellmunt et al. in J Clin Oncol, 27: 4454-4461, 2009). There is an estimated overall survival of 9-15 months in metastatic bladder cancer in those who receive the standard of care platinum-based chemotherapy (Von der Maase et al. in J Clin Oncol, 23:4602-4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012). The median survival, however, is significantly reduced after relapse in patient treated with platinum chemotherapy to less than 7 months (Bellmunt et al. in J Clin Oncol, 27: 4454-4461, 2009). Thus, this approach is preferred for patients who can tolerate this treatment as first-line chemotherapy (Gupta et al. in Cancer, 9(15):1-14, 2017). Until recently, there were few treatment options for those patients with poor performance status who are ineligible to receive cisplatin including renal insufficiency and multiple comorbidities or had disease progression after receiving platinum-based chemotherapy (Gupta et al. in Cancer, 9(15):1-14, 2017). With further understanding of tumor immune evasion, systemic immunotherapy which utilizes the patient's own immune system directly to eradicate and target neoplastic cells, has now been approved for urothelial bladder cancer. Monoclonal antibodies that target programmed cell death protein 1 (PD-1), including Nivolumab and Pembrolizumab, and its ligand, PD-L1, including Atezolizumab, Durvalumab, Avelumab, have all been investigated and approved in the setting of metastatic refractory urothelial cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602-4608, 2005; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). Atezolizumab and Pembrolizumab have also been approved as first-line therapy in the setting of cisplatin-ineligible metastatic bladder cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). Those that target cytotoxic T-lymphocyte-associated protein 4, including Ipilimumab and Tremelimumab, have also been investigated and further studies are ...

Expression of PD‐L1 and CTLA‐4 in female urethral carcinoma

“…PD‐L1 is expressed in some of urothelial cancers and exhibits an antitumor effect by suppressing activation of T cells or the anti‐tumorigenic immune system. Both anti‐PD‐L1 and anti‐CTLA‐4 antibodies have been shown to suppress tumor progression through these mechanisms . Currently available molecular markers are insufficient to predict the potential for tumor recurrence and progression precisely.…”

“…The European Association of Urology guideline recommends surgical resection in combination with neoadjuvant chemotherapy for the management of advanced urethral carcinoma. 5 This systemic chemotherapy is found to be effective in 72% of cases and is associated with prolonged overall survival. However, no further postoperative therapies that significantly improve patient outcomes have been established.…”

“…Both anti-PD-L1 and anti-CTLA-4 antibodies have been shown to suppress tumor progression through these mechanisms. 5 Currently available molecular markers are insufficient to predict the potential for tumor recurrence and progression precisely. PD-L1 is expressed on antigen-presenting cells, such as human monocytes, as well as activated human and murine dendritic cells.…”

Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches

“…Currently, there are five anti‐PD‐1/PD‐L1 ICB immunotherapeutic drugs approved by the FDA for the treatment of bladder and other urothelial carcinomas (UCs), including three anti‐PD‐L1 and two anti‐PD‐1 antibodies (Table ).…”

Bacillus Calmette–Guérin strain differences as the basis for immunotherapies against bladder cancer

“…Recombinant BCG strains expressing interferon-a are also currently being researched. 71 Other approaches include cancer vaccines, gene therapies and chemoradiation potentiation agents. Immune checkpoint inhibitors (e.g.…”