Image-guided TRAIL-enhanced CAR T-cell immunotherapy

图像引导 TRAIL 增强的 CAR T 细胞免疫疗法

• 批准号: 9892971
• 负责人: Vladimir Ponomarev
• 金额: $ 56.78万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892971
• 关键词: Adoptive Immunotherapy; Adverse effects; Affect; Antigens; Apoptosis; Apoptotic; Biological; Breast; Cancer Center; Cancer Patient; Cells; Cellular immunotherapy; Cessation of life; Chemotherapy and/or radiation; Clinic; Clinical Research; Clinical Trials; Colorectal; Complement; Disease remission; Exhibits; FOLH1 gene; Genes; Genetic Engineering; Glioma; Goals; Hormonal; Image; Immune; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Ligands; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Measurable; Measurement; Mediating; Membrane; Modality; Monitor; Mus; Normal Cell; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Prostate; Protocols documentation; Radiation; Radiation therapy; Radiopharmaceuticals; Recombinants; Reporter Genes; Resistance; Stimulus; Surface; T cell therapy; T-Cell Activation; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; TNF gene; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Time; Translating; Translations; Tumor Immunity; Work; Xenograft Model; anti-PSMA; antigen-specific T cells; base; cancer cell; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical application; clinically relevant; cytotoxicity; design; effector T cell; factor A; human model; image guided; immunogenic; improved; innovation; irradiation; neoplastic cell; non-invasive imaging; non-invasive monitor; novel; overexpression; pre-clinical; prostate cancer model; receptor; response; theranostics; trafficking; treatment response; tumor; tumor eradication

PROJECT SUMMARY Cancer cells have been shown to be sensitive to apoptotic stimulus of tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL), whereas normal cells showed very little response. TRAIL was shown to be active as a single agent and exhibited synergistic activity with certain chemotherapeutic agents or radiotherapy, causing marked regression or complete remission of tumors. There is increasing evidence that membrane-bound TRAIL expressed on the surface of activated T-lymphocytes can enhance T-cell effector function and augment T-cell tumoricidal activity. The ability to genetically engineer primary T-cells creates new and highly promising prospects for tumor immunity and cancer treatment. The transduction of T-cells with genes encoding chimeric antigen receptors enables T-cell recognition of antigens that are either poorly immunogenic or ignored by the immune system. In addition, the genetically engineered expression of therapeutic ligands (e.g. TRAIL) by T-cells can potently increase their tumoricidal activity. New strategies for tumor sensitization to TRAIL-based immunotherapies and modulation of TRAIL resistance are being developed and some can be translated to the clinic. Our central theme and hypothesis is that TRAIL overexpression by T- cells results in augmented apoptosis in tumor cells and that radiation and/or chemotherapy positively affect TRAIL-mediated tumor apoptosis during T-cell adoptive immunotherapy and can be used as a synergistic approach to enhance T-cell tumor targeting and effector function. In this application we propose to develop and test a novel theranostic approach to augment tumor apoptosis in a prostate cancer model with heterogeneous PSMA levels using TRAIL overexpression by chimeric antigen receptor (CAR)-grafted PSMA-specific T-cells. We will assess the effect of membrane-bound vs. secretable forms of TRAIL expressed by PSMA-specific T-cells on their ability to kill PSMA-positive and -negative targets. We will determine whether radiation/chemotherapy-induced “sensitization” of TRAIL-resistant tumor cells correlates with an improved T-cell tumoricidal function. Ultimately, we will assess the feasibility and sensitivity of PET imaging to monitor PSMA-specific T-cell activation and delivery of TRAIL therapeutic payloads to the tumor. These processes will be monitored using multi-reporter gene and conventional imaging by assessing T- cell tumor targeting and activation as well as tumor response. Our proposal complements on-going clinical studies at MSK and other cancer centers by exploring new strategies designed to enhance T-cell effector function and improve treatment response. The results will provide preclinical support and justification to move toward clinical application in patients with prostate and other cancers undergoing immunotherapy with genetically modified T-cells. !

项目概要 癌细胞已被证明对肿瘤坏死因子α相关的凋亡刺激敏感 凋亡诱导配体（TRAIL），而正常细胞几乎没有反应。 TRAIL 被证明是 作为单一药物具有活性并与某些化疗药物表现出协同活性或 放射治疗，导致肿瘤明显消退或完全缓解。越来越多的证据表明 活化T淋巴细胞表面表达的膜结合TRAIL可以增强T细胞效应 功能并增强 T 细胞的杀肿瘤活性。对原代 T 细胞进行基因改造的能力创造了新的 肿瘤免疫和癌症治疗的前景非常广阔。 T 细胞的转导 编码嵌合抗原受体的基因使 T 细胞能够识别抗原，这些抗原要么很弱 具有免疫原性或被免疫系统忽视。此外，基因工程表达 T 细胞的治疗配体（例如 TRAIL）可以有效增强其杀肿瘤活性。新策略 肿瘤对基于 TRAIL 的免疫疗法的敏感性和 TRAIL 耐药性的调节正在开发中 有些可以转化为临床。我们的中心主题和假设是 T- TRAIL 过度表达 细胞导致肿瘤细胞凋亡增加，并且放疗和/或化疗会产生积极影响 T 细胞过继免疫治疗期间 TRAIL 介导的肿瘤细胞凋亡，可用作协同药物 增强 T 细胞肿瘤靶向和效应器功能的方法。 在本申请中，我们建议开发和测试一种新的治疗诊断方法来增强肿瘤细胞凋亡 使用嵌合抗原 TRAIL 过表达的具有异质 PSMA 水平的前列腺癌模型 受体 (CAR) 移植的 PSMA 特异性 T 细胞。我们将评估膜结合与分泌的效果 PSMA 特异性 T 细胞表达的 TRAIL 形式，影响其杀死 PSMA 阳性和阴性靶标的能力。 我们将确定放疗/化疗是否诱导 TRAIL 耐药肿瘤细胞“致敏” 与 T 细胞杀肿瘤功能的改善相关。最终，我们将评估可行性和敏感性 PET 成像监测 PSMA 特异性 T 细胞激活以及 TRAIL 治疗有效负载的递送 瘤。这些过程将通过评估T-使用多报告基因和常规成像进行监测 细胞肿瘤靶向和激活以及肿瘤反应。 我们的提案通过探索新的方法来补充 MSK 斯隆和其他癌症中心正在进行的临床研究 旨在增强 T 细胞效应功能并改善治疗反应的策略。结果将 为前列腺癌患者的临床应用提供临床前支持和理由 其他癌症正在接受转基因 T 细胞的免疫治疗。 ！