Abstract
Advanced bladder cancer is still an area of high unmet need even with the use of immune checkpoint inhibitors and antibody drug conjugates. Therefore, transformatively novel therapeutic approaches are needed. Xenogeneic cells are capable of inducing potent innate and adaptive immune rejection responses, which properties could turn xenogeneic cells into an immunotherapeutic agent. Here, we investigated the anti-tumor effects of intratumoral xenogeneic urothelial cell (XUC) immunotherapy alone and in combination with chemotherapy in two murine syngeneic models of bladder cancer. In both bladder tumor models, intratumoral XUC treatment suppressed tumor growth, and the efficacy was enhanced with chemotherapy. The experiments on mode of action for intratumoral XUC treatment found that the remarkable local and systemic anti-tumor effects were achieved with significant intratumoral immune cell infiltration and systemic activation of immune cell cytotoxic activity, cytokine IFNγ production and proliferation ability. The intratumoral XUC alone and combined treatment increased T cell natural killer cell infiltration into tumors. In the bilateral tumor model with intratumoral XUC monotherapy or combined therapy, the uninjected tumors at the other side also simultaneously demonstrated significant tumor growth delay. Consequently, intratumoral XUC treatment alone and the combination resulted in elevated chemokine CXCL9/10/11 levels. These data suggest that intratumoral XUC therapy may be useful in the treatment of advanced bladder cancer as a local therapy that injects xenogeneic cells into either primary or distant tumors. By exerting both local and systemic anti-tumor effects, this new treatment would complete the comprehensive cancer management along with systemic approaches.