Current Landscape of Immune Checkpoint Inhibitors for Metastatic Urothelial Carcinoma: Is There a Role for Additional T-Cell Blockade?

Simple Summary Immune checkpoint inhibition has played a significant role in the treatment landscape of urothelial carcinoma due to the highly immunogenic tumor microenvironment. However, there remains a suboptimal response to therapy by patients due to resistance to therapy. New paradigms of treatment using PD-1, PD-L1, and CTLA-4 inhibitors are vital for addressing resistance to treatment. In this review, we describe preclinical and clinical literature on immune checkpoint inhibitors in urothelial carcinoma. Specifically, we propose the use of combinatorial therapy of already FDA-approved immune checkpoint inhibitors to boost the response of the immune system. There are currently no FDA-approved therapies that combine PD-1/PD-L1 inhibitors with CTLA-4 inhibitors despite approvals in other solid tumors. Successful implementation of combined PD-1/PD-L1 and CTLA-4 inhibitors could significantly improve patient response. Here, we discuss preclinical and clinical research findings to broaden the knowledge of immune checkpoint inhibitors for urothelial carcinoma therapy.Abstract Urothelial carcinoma (UC) is the most common form of bladder cancer (BC) and is the variant with the most immunogenic response. This makes urothelial carcinoma an ideal candidate for immunotherapy with immune checkpoint inhibitors. Key immune checkpoint proteins PD-1 and CTLA-4 are frequently expressed on T-cells in urothelial carcinoma. The blockade of this immune checkpoint can lead to the reactivation of lymphocytes and augment the anti-tumor immune response. The only immune checkpoint inhibitors that are FDA-approved for metastatic urothelial carcinoma target the programmed death-1 receptor and its ligand (PD-1/PD-L1) axis. However, the overall response rate and progression-free survival rates of these agents are limited in this patient population. Therefore, there is a need to find further immune-bolstering treatment combinations that may positively impact survival for patients with advanced UC. In this review, the current immune checkpoint inhibition treatment landscape is explored with an emphasis on combination therapy in the form of PD-1/PD-L1 with CTLA-4 blockade. The investigation of the current literature on immune checkpoint inhibition found that preclinical data show a decrease in tumor volumes and size when PD-1/PD-L1 is blocked, and similar results were observed with CTLA-4 blockade. However, there are limited investigations evaluating the combination of CTLA-4 and PD-1/PD-L1 blockade. We anticipate this review to provide a foundation for a deeper experimental investigation into combination immune checkpoint inhibition therapy in metastatic urothelial carcinoma.