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。没有明显改善 过去三十年晚期 BCa 的总体生存率。免疫检查点免疫治疗 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 到这个治疗。正在探索各种策略，包括与其他疗法的组合 增强免疫治疗的疗效。在 VA Career Development Award-2 和 VA 的资助下 优点，我们开发了一种BCa特异性PLZ4-纳米卟啉（PNP），它结合了成像引导 化疗、光动力和光热疗法整合到一个平台中。三种疗法均具有 已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 通过联合使用免疫检查点抑制剂可以增强免疫治疗的疗效 免疫疗法包括使用 PNP 的化疗、光动力疗法和光热疗法。因为 PNP 可以 针对小鼠BCa细胞系MB49，我们将首先在免疫活性小鼠中进行功效研究 携带MB49同基因肿瘤。 最近，我们开发了 人源化小鼠中，免疫细胞 宿主小鼠源自人类。我们将向这些小鼠植入患者来源的异种移植物 (PDX) 为了验证 MB49 细胞，从未经选择和未培养的人类患者癌症组织中开发而来 小鼠的线研究。然后我们将这些研究转化为 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。由于我们已经举办了 与美国食品和药物管理局 PNP 进行 IND（研究性新药）前咨询， 该项目的成功完成可以开展将 PNP 与 BCa 免疫疗法相结合的临床试验。