ReviewPD-1/PD-L1 Combinations in Advanced Urothelial Cancer: Rationale and Current Clinical Trials
Section snippets
Epidemiology of Bladder Cancer
Worldwide, bladder cancer (BC) is the ninth most common cancer. Urothelial carcinoma (UC) is the predominant (90%) histologic subtype. This histology can occur throughout the urinary tract, but is most frequently found in the bladder.1 In 2012, 429,800 new cases of BC arose, with the highest incidences in Western Europe and Northern America.2, 3 Within that year, there were 165,100 deaths attributed to the disease.2 Focusing on the United States in 2018, BC will be newly diagnosed in 81,190
Recent Advancements in UC Immunotherapy
Immune checkpoints function to induce immune self-tolerance. T-cell effector activity must be tightly regulated to prevent self-damage from physiologic defensive responses and the induction of autoimmunity. Many immune checkpoints are known to exist; however, the majority of research and clinical implementation has been focused on antagonists of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and the programmed death receptor (PD-1) and programmed death receptor ligand (PD-L1).7 Although
Reversal of T-cell Exhaustion
Chronic antigen stimulation in the absence of co-stimulatory signals “exhausts” effector cells.44 As the presence and severity of exhaustion are correlated with surface presentation of inhibitory receptors, and is in large part attributed to their signaling, reversal of exhaustion would entail blocking these receptors. PD blockade in lymphocytic choriomeningitis virus infection models rescues anti-viral immunity,45 and PD inhibition has shown efficacy in multiple tumor types. Although
Combined Chemotherapy and ICI
Rather than T-cell suppression, immune inaction can result from immune ignorance. Tumors not presenting immunogenic antigen, named cold tumors, may pass as “self.” Generating a response to PD blockade, then, would entail manufacturing exposure of antigen to the immune system. Chemotherapy is a potential method, yet it causes a range of host toxicities, including a weakened immune system. Synergy in concurrent chemo- and immunotherapy may be seem counterintuitive. CTLA-4 inhibition (ipilimumab)
Conclusion
In the treatment of advanced UC, CI has produced outcomes that compare with or improve on those of platinum-based chemotherapy. The durability of response is a particular advantage for CI. Significant responses, however, occur in a minority of patients, leaving anti-tumor immunity untapped in the majority. Growing understanding of the TME and its diversity among cancers and among patients will provide information on the likelihood of immunotherapy success. Furthermore, this understanding will
Disclosure
The authors have stated that they have no conflicts of interest.
Acknowledgments
This research is supported in part by the New York University Clinical and Translational Science Award grant UL1 TR001445, from the National Center for Advancing Translational Sciences, National Institutes of Health.
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Cited by (8)
A novel 17 apoptosis-related genes signature could predict overall survival for bladder cancer and its associations with immune infiltration
2022, HeliyonCitation Excerpt :Bacillus Calmette-Guerin, as an efficient method, was found to be a highly effective treatment among BC patients [12]. As immune checkpoint inhibitors, PD-1/PD-L1 inhibitors were designed to block molecules that influenced immune responses and decreased the strength of immune responses, ultimately affecting T cell activation [13, 14]. Cytotoxic T cell antigen, as another vital immune checkpoint inhibition, could mobilize the immune system against BC [15, 16].
Programmed Death 1 and Programmed Death Ligand 1 Inhibitors in Advanced and Recurrent Urothelial Carcinoma: Meta-analysis of Single-Agent Studies
2020, Clinical Genitourinary CancerCitation Excerpt :Thus, tumors lacking immune cells (cold tumors) are less likely to respond. Quantitative measurement of immune cells within different compartments of the tumor requires further improvement and increased rigor in current assays.21 Our objective was to summarize the current state of ICI therapy in the setting of failure to first-line therapy in locally advanced or metastatic urothelial cancer; and to evaluate the response rates among the reported clinical trials.
Immunotherapy for Metastatic Urothelial Carcinoma
2021, Bladder Cancer: A Practical Guide