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: 10371094
• 负责人: Vladimir Ponomarev
• 金额: $ 56.56万
• 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/10371094
• 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. !

项目摘要 癌细胞已被证明对肿瘤坏死因子α相关的凋亡刺激敏感 凋亡诱导的配体（TRAR），而正常细胞的反应很少。足迹被证明是 作为单一药物活跃并与某些化学治疗剂或 放疗，导致明显的消退或完全缓解肿瘤。有越来越多的证据表明 在活化的T淋巴细胞表面表达的膜结合步道可以增强T细胞效应器 功能和增强T细胞肿瘤活性。基因设计主要T细胞的能力创造了新的 以及肿瘤免疫学和癌症治疗的高度承诺前景。 T细胞的翻译与 编码嵌合抗原受体的基因使T细胞识别抗原的T细胞识别要么很差 免疫原性或被免疫系统忽略。另外，一般设计的表达 T细胞通过T细胞的治疗配体（例如TRAIL）可能会增加其结核病活性。新的策略 肿瘤对基于步道的免疫疗法的敏感性和越野阻力的调节 有些可以转化为诊所。我们的中心主题和假设是T-的轨迹过表达 细胞导致肿瘤细胞的凋亡增大，并且放射和/或化学疗法积极影响 在T细胞收养免疫疗法期间径向介导的肿瘤凋亡，可以用作协同作用 增强T细胞肿瘤靶向和效应子功能的方法。 在此应用中，我们建议开发和测试一种新型的热方法来增强肿瘤凋亡 使用嵌合抗原的TRAIL过表达具有异质PSMA水平的前列腺癌模型 接收器（CAR）嫁接的PSMA特异性T细胞。我们将评估膜结合与分泌的影响 PSMA特异性T细胞表达的TRAIL形式，其杀死PSMA阳性和阴性靶标的能力。 我们将确定放射/化学疗法诱导的耐痕量肿瘤细胞的“敏化” 与改善的T细胞肿瘤功能相关。最终，我们将评估可行性和敏感性 PET成像以监视PSMA特异性T细胞激活和TRAIL热有效载荷的传递 瘤。这些过程将通过评估T-来使用多重孢子基因和常规成像来监测这些过程 细胞肿瘤靶向和激活以及肿瘤反应。 我们在MSK和其他癌症中心正在进行的临床研究的提案完成，探索新的 旨在增强T细胞效应子功能和改进治疗响应的策略。结果将 提供临床前支持和理由，以在前列腺患者和 其他癌症接受免疫疗法的癌症，具有一般修饰的T细胞。 呢