Petros Grivas, MD
Bladder cancer is very common and can cause significant morbidity, mortality, emotional distress, and financial burden for patients, families, societies, and healthcare systems worldwide. The most common histologic type is urothelial carcinoma (UC), which can affect the renal pelvis, ureter, bladder (most common site), and urethra. Long-term survival rates for locally advanced (with extravesical and/ or node-positive disease) and metastatic disease remain dismal, with an overall survival (OS) of 9 to 15 months and 5-year OS rate of 5% for metastatic cancer, even with platinum-based chemotherapy, which is the standard of care. The entire disease spectrum requires the development of new agents that are feasible and can improve outcomes. In that context, immune checkpoint inhibitors (ICIs), with their favorable safety and antitumor activity profiles, have heralded a new era in UC treatment.
The primary molecular targets for ICIs are PD-1, PD-L1, and CTLA-4 checkpoints, which act as coinhibitory signals blocking antitumor effector T-cell responses, thereby downregulating antitumor response.1
PD-1 is a transmembrane protein expressed on activated T cells that interacts with PD-L1 (B7-H1 or CD274), which is expressed on antigen-presenting cells and many types of tumor cells.2,3
This interaction leads to suppression of T-cell receptor–mediated effector functions and inhibits proliferation of antigen-specific CD8-positive T cells.3
Cells of immunologically responsive tumors often up-regulate PD-L1 expression, thereby facilitating immune escape. By blocking either PD-1 or PD-L1, ICIs reinvigorate antitumor T-cell-mediated immune responses.4
CTLA-4 is structurally related to CD28, a costimulatory signal that plays a vital role in T-cell activation.5
By competitively binding to its ligands B7.1 and B7.2, CTLA-4 blocks CD28-mediated costimulatory signaling and thus inhibits T-cell activation.6,7
ICIs that block CTLA-4 will thus lead to reactivation of antitumor effector T-cell response mechanisms.8
A plethora of clinical trials employing ICIs and targeted agents against related immune pathways are ongoing in diverse UC spaces and treatment settings. Below are updates in the development of ICIs across UC treatment settings; however, because data emergence is very dynamic and continuous in this research field, this is not a comprehensive list.
Nonmuscle-Invasive Bladder Cancer
The International Bladder Cancer Group has developed refined recommendations on definitions, endpoints, and clinical trial designs for nonmuscle-invasive bladder cancer (NMIBC) to support alignment and harmonization across clinical trials.9
These guidelines also provide a conceptual framework regarding the use of comparator arms and time points for assessment in the settings of Bacillus Calmette–Guérin (BCG)–naïve, BCG-relapsing, and BCG-unresponsive disease.