Bladder cancer is a paradigm of solid tumor malignancy (1), exhibiting significant tumor heterogeneity with elaboration of a broad range of biomarkers, moderate responsiveness to radiation and chemotherapy (1,2), and features that support the existence of solid tumor stem cell functions (3). We have used the xenograft model as a tissue amplifier (4), with subcutaneous or orthotopic implantation of tiny fragments of human bladder cancer, as a mechanism to study the characteristics of this disease, and to model novel treatments (5). We have demonstrated features underlying the heterogeneity of cytotoxic responsiveness (5), and the impact of multi-agent treatment. Initial clinical modeling of chemotherapy for bladder cancer showed modest responsiveness to single agent treatment (6), but our randomized trial showed statistically significant and clinically relevant improvements from multi-drug regimens (7). This led to neoadjuvant modeling, with a trajectory from single agents (6) to combined modality regimens (8,9), the latter showing statistically and clinically significant improvements in survival that created a paradigm shift. It appears that a plateau has been achieved for cytotoxic treatment, but immune modulation now appears highly promising in bladder cancer. However, the immune paresis associated with the xenograft model has limited the preclinical assessment of the utility of T-cell targeting via PD-L1 and lymphocyte function release via PD-L1 inhibition in this disease.