Potentiation of Immunotherapy with targeted nanoporphyrin in bladder cancer

摘要 膀胱癌(BCA)是退伍军人最常见的癌症之一。在以下方面没有显著改善 在过去的30年中，晚期BCA的总体存活率。利用免疫检查点进行免疫治疗 在这种疾病中，抑制剂显示出良好的抗肿瘤活性。然而，只有不到20%的患者有反应 接受这种治疗。正在探索各种策略，包括与其他疗法的结合，以 增强免疫治疗的疗效。由退伍军人事务部职业发展奖-2和退伍军人事务部资助 优点，我们开发了一种BCA特异性的PLZ4纳米卟啉(PNP)，它结合了成像引导 将化学疗法、光动力疗法和光热疗法整合到一个平台中。这三种疗法都有 已被证明可以用癌症疫苗加强免疫治疗。在这里，我们建议确定是否 使用免疫检查点抑制剂的免疫治疗效果可以通过联合 使用PNP进行化疗、光动力和光热疗法的免疫疗法。因为PnP可以 以小鼠BCA细胞系MB49为靶点，我们将首先在具有免疫能力的小鼠身上进行疗效研究 携带49元同基因肿瘤。 最近，我们开发了 人源化的小鼠体内的免疫细胞 宿主老鼠是从人类进化而来的。我们将把患者来源的异种移植物(PDX)植入这些小鼠体内 从未经挑选和培养的人类癌症组织中开发，以验证MB49细胞 在小鼠身上进行的直线研究。然后我们将把这些研究转化为BCA转基因小鼠，以确定PNP是否 可以加强免疫治疗。还将研究抗药性的机制。因为我们已经举行了一次 与美国食品和药物管理局就PNP进行IND(研究新药)前咨询， 该项目的成功完成可能导致在BCA中将PNP与免疫疗法相结合的临床试验。

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.