Potentiation of Immunotherapy with targeted nanoporphyrin in bladder cancer

靶向纳米卟啉增强膀胱癌的免疫治疗

• 批准号: 9898243
• 负责人: CHONG-XIAN PAN
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898243
• 关键词: Abscopal effect; Affect; C57BL/6 Mouse; Cancer Patient; Cancer Vaccines; Cancer cell line; Canis familiaris; Cell Line; Cells; Chemosensitization; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Consultations; Department of Defense; Diagnostic; Disease; Disease Progression; Doxorubicin; Funding; Future; General Population; Genetic; Goals; Grant; Hematopoietic stem cells; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunotherapy; Implant; Infiltration; Investigational Drugs; Isogeneic graft; K-Series Research Career Programs; Kidney Failure; Lead; Ligands; Light; Local Therapy; Lung; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical; Modeling; Morphology; Mouse Cell Line; Mus; Names; Neoplasm Metastasis; Obstruction; PUVA Photochemotherapy; Patients; Phase I Clinical Trials; Phototherapy; Porphyrins; Procedures; Production; Recurrence; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Translating; Treatment Efficacy; Treatment outcome; Tumor Immunity; UPK2 gene; United States Food and Drug Administration; Veterans; Xenograft procedure; anti-PD1 antibodies; base; cancer cell; chemotherapeutic agent; chemotherapy; clinically relevant; cytokine; design; efficacy study; humanized mouse; image guided; immunogenic cell death; improved; in vivo; macromolecule; mortality; nanoparticle; novel therapeutics; photothermal therapy; prevent; programmed cell death ligand 1; programs; resistance mechanism; response; tumor; tumor growth; tumor microenvironment; urinary

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.

抽象的 膀胱癌（BCA）是退伍军人中最常见的癌症之一。没有显着改善 在过去的三十年中，高级BCA的总生存期。免疫检查点的免疫疗法 抑制剂在该疾病中显示出有希望的抗肿瘤活性。但是，不到20％的患者反应 对此治疗。正在探索各种策略，包括与其他疗法组合的组合 增强免疫疗法的功效。在VA职业发展奖2和VA的资助下 优点，我们开发了BCA特异性的PLZ4-纳米卟啉（PNP），它结合了成像引导 化学疗法，光动力和光热疗法用于单个平台。所有三种疗法都有 显示可通过癌症疫苗增强免疫疗法。在这里，我们建议确定是否 可以通过合并来增强免疫检查点抑制剂免疫疗法的功效 使用PNP进行化学疗法，光动力和光热疗法的免疫疗法。因为PNP可以 靶向小鼠BCA细胞系MB49，我们将首先进行免疫能力小鼠的功效研究 携带MB49合成肿瘤。 最近，我们开发了 人性化小鼠，其中的免疫细胞 宿主小鼠源自人类。我们将植入这些小鼠患者衍生的异种移植物（PDX） 从未选择和未养殖的人类患者癌组织开发，以验证MB49细胞 小鼠的线研究。然后，我们将研究将研究转化为BCA转基因小鼠，以确定PNP是否 可以增强免疫疗法。还将研究电阻机制。由于我们已经持有 与美国食品药品监督管理局（PNP 该项目的成功完成可能会导致一项临床试验，以将PNP与BCA的免疫疗法相结合。