Systemic anti-CTLA-4 and intravesical Bacille-Calmette-Guerin therapy in non-muscle invasive bladder cancer: Is there a rationale of synergism?

Although intravesical instillation of Bacille-Calmette-Guerin (BCG) immunotherapy was approved many decades ago as a first line therapy for intermediate to high-risk non-muscle invasive bladder cancer, its long-term efficacy is still arguable as a proportion of up to 30-40% of patients will develop recurrence or progression of their disease. Based on currently available data on the clinical application of checkpoint inhibitors in solid tumors, the mucosa-associated lymphoid tissue seems to be a main target for anti-CTLA-4 antibodies. In this manuscript we hypothesize that the combination of anti-CTLA-4 therapy with BCG might enhance the immune activity in the bladder submucosal tissue, and subsequently, improve oncological outcomes of NMIBC.