Potential cellular intravesical therapy for non-muscle invasive bladder cancer: Nectin-4 targeted CAR-T cell therapy

Abstract

Bladder cancer poses a significant global health challenge, particularly with its prevalence in males and the increasing incidence rates in Europe. While non-muscle invasive bladder cancer can be managed with localized treatments, its recurrence remains a concern. Intravesical Bacillus Calmette-Guérin therapy triggers an immune response against cancer cells, yet recurrences post- transurethral resection of bladder tumor persist. Thus, innovative strategies are needed. We propose the use of Nectin-4 targeted chimeric antigen receptor T cell therapy to prevent non-muscle invasive bladder cancer recurrence and progression. Nectin-4 is expressed in non-muscle invasive bladder cancer, making it an ideal target. CAR-T cells engineered with Nectin-4 receptors can specifically eliminate cancer cells. By directly applying these cells intravesically, the limitations of CAR-T cell access to solid tumors are circumvented. However, challenges persist, such as the immunosuppressive microenvironment of bladder cancer. This can be addressed by combining intravesical Bacillus Calmette-Guérin with CAR-T therapy or utilizing immune checkpoint inhibitors. CAR-T therapy-related toxicities, like cytokine release syndrome, can be managed with IL-6 and IL-1 receptor inhibitors. Our hypothesis suggests that Nectin-4 targeted CAR-T cells have the potential to revolutionize bladder cancer treatment. This therapy could not only eliminate cancer cells but also prevent recurrence and progression by inducing immune memory. Although further research is needed, this innovative approach shows promise in the treatment of non-muscle invasive bladder cancer.