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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要