Combination of Immune Checkpoint Inhibitors in Urothelial Carcinoma: PD-1/PD-L1 and CTLA-4

Abstract

Urothelial carcinoma is the most common form of bladder cancer and is the variant with the most immunogenic response. This makes urothelial carcinoma an appropriate candidate for immunotherapy in the form of immune checkpoint inhibitors. Immune checkpoint inhibitors are antibodies directed against immune checkpoint-related molecules expressed on tumor-infiltrating lymphocytes. There have been multiple studies on the role of the immune checkpoint molecule, PD-1 on T-cells and its interaction with the ligand PD-L1. Moreover, CTLA-4 is a different checkpoint also expressed on T-cells in urothelial carcinoma. The blockade of CTLA4 can lead to the reactivation of lymphocytes by preventing apoptosis and anergy. The only FDA-Approved immune checkpoint inhibitors for metastatic urothelial carcinoma target the PD-1/PD-L1 pathway. However, the overall response rate and progression-free survival rates of these drugs are not sufficient in the patient population. In this review, the current immune checkpoint inhibition (ICI) treatment landscape is explored with an emphasis on combination therapy in the form of PD-1/PD-L1 with CTLA-4. Investigation of the current literature on ICI in in-vivo experiments shows a decrease in tumor volumes and size when PD-1/PD-L1 is blocked, and this result is replicated in CTLA-4 blockade. However, there are limited preclinical models testing tumor response in combination blockade of CTLA-4 in the presence of PD-1/PD-L1 blockade. In this review, a proposal on canine organoid bladder samples as a complement to transgenic mice for preclinical drug testing is also explored. We anticipate this review to be a foundation for a deeper experimental investigation into combination therapy in the form of PD-1/PD-L1 and CTLA-4 blockade in metastatic urothelial carcinoma.