Potentiation of Immunotherapy with targeted nanoporphyrin in bladder cancer

摘要 膀胱癌（BCa）是退伍军人中最常见的癌症之一。没有明显改善， 在过去的三十年里，晚期BCa的总生存率。使用免疫检查点的免疫治疗 抑制剂在这种疾病中显示出有希望的抗肿瘤活性。然而，只有不到20%的患者有反应， 这种治疗。正在探索各种策略，包括与其他疗法联合， 增强免疫治疗的效果。随着VA职业发展奖的资助-2和VA 优点，我们开发了一种BCa特异性PLZ 4-纳米卟啉（PNP），结合成像引导 将化疗、光动力和光热疗法整合到一个平台中。这三种疗法都有 被证明可以增强癌症疫苗的免疫治疗。在这里，我们建议确定是否 免疫检查点抑制剂的免疫治疗功效可以通过联合 免疫疗法与化学疗法、使用PNP的光动力疗法和光热疗法。因为PNP可以 针对小鼠BCa细胞系MB 49，我们将首先在免疫活性小鼠中进行疗效研究 携带MB 49同基因肿瘤。 最近，我们开发了 人源化小鼠，其中免疫细胞的免疫细胞 宿主小鼠来源于人类。我们将在这些小鼠中植入患者来源的异种移植物（PDX）， 从培养的和未培养的人类患者癌组织中开发，以验证MB 49细胞 在小鼠中的线研究。然后，我们将研究转化为BCa转基因小鼠，以确定PNP是否 可以增强免疫治疗。还将研究耐药机制。由于我们已经举行了一次 与美国食品药品监督管理局就PNP进行IND（研究性新药）前咨询， 该项目成功完成可导致联合收割机PNP与BCa免疫治疗相结合的临床试验。

ABSTRACT Bladder cancer (BCa) is one of the most common cancers in veterans. There is no significant improvement in overall survival for advanced BCa over the last three decades. Immunotherapy with immune checkpoint inhibitors showed promising anti-tumor activity in this disease. However, less than 20% of patients respond to this treatment. Various strategies, including combination with other therapies, are being explored to enhance the efficacy of immunotherapy. With the funding of the VA Career Development Award-2 and VA Merit, we developed a BCa-specific PLZ4-nanoporphyrin (PNP) that combines imaging-guided chemotherapy, photodynamic and photothermal therapies into a single platform. All three therapies have been shown to potentiate immunotherapy with cancer vaccines. Here we propose to determine whether the efficacy of immunotherapy with an immune checkpoint inhibitor can be enhanced via combining immunotherapy with chemotherapy, photodynamic and photothermal therapies using PNP. Because PNP can target the mouse BCa cell line MB49, we will first conduct the efficacy studies in immunocompetent mice carrying MB49 syngeneic tumors. Recently, we developed humanized mice in which the immune cells of the host mice are derived from humans. We will implant into these mice patient-derived xenografts (PDX) that are developed from unselected and uncultured human patient cancer tissues in order to validate the MB49 cell line studies in mice. We will then translate the studies into BCa transgenic mice to determine whether PNP can potentiate immunotherapy. Mechanisms of resistance will also be studied. Since we have already held a pre-IND (Investigational New Drug) consultation with the US Food and Drug Administration for PNP, successful completion of this project can lead to a clinical trial to combine PNP with immunotherapy in BCa.