Brigham & Women's Hospital, Harvard Medical School
Introduction: Immunotherapy with PD-1 inhibitors can be augmented by synergistic use of other treatment modalities and we sought to develop a photodynamic therapy (PDT) regimen. PDT relies on the accumulation of a photosensitizer (nanoporphyrin) that, when activated by light, generates reactive oxygen species (ROS) to kill cancer cells. We developed a bladder cancer-targeting molecule PLZ4-nanoporphyrin (PNP) which uses the peptide PLZ4 to specifically bind bladder cancer cells. We aimed to show that PNP activation and therapy potentiated the effect of anti-PD-1 therapy in bladder cancer cells. Methods: PNP was prepared by conjugation of a nanoporphyrin with PLZ4. The efficacy of PNP and anti-PD-1 therapy was assessed in vivo by treating a transgenic mouse model of bladder cancer (Ras/SV40) and trending tumor reduction and overall survival. Mice were injected subcutaneously with the mouse bladder cell line BBN963 and the efficacy of PNP and anti-PD-1 therapy was further assessed in vivo by assessing tumor reduction. Results: Compared with the median overall survival of 33.7 days of the control, anti-PD-1 therapy and PNP alone improved the overall survival of Ras/SV40 mice by 11 and 19 days to 44.8 (P = 0.0123) and 52.6 days (P = 0.0054), respectively. In contrast, the combination of anti-PD-1 immunotherapy and PNP increased the overall survival by over 40 days (P = 0.0001) (Figure 1a). To further study the synergistic effects, tumor models were generated by implanting laboratory mice with BBN963 cells subcutaneously. Following laser treatment to activate PNP and potentiate PDT, tumors treated with anti-PD-1 therapy alone, PNP alone, and anti-PD-1 and PNP in combination had a 40.25% (P = 0.0003), 80.72% (P < 0.0001), and 93.03% (P < 0.0001) reduction, respectively (Figure 1b). Conclusions: PDT with PNP promotes bladder tumor cell death and activation of the immune system. Using mouse models of bladder cancer, PNP potentiates the effect of anti-PD-1 therapy through reduction of tumor burden and improved overall survival, suggesting an enticing synergistic treatment regimen in bladder cancer. Further studies and clinical trials are needed to determine the safety and efficacy of this regimen in humans. SOURCE OF Funding: VA Merit Review Grant.
