Imaging the efficacy of TRAIL-enhanced cancer immunotherapy

TRAIL 增强癌症免疫疗法的功效成像

• 批准号: 9387986
• 负责人: Prasad S. Adusumilli
• 金额: $ 22.55万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-05 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387986
• 关键词: Adoptive Immunotherapy; Adverse effects; Affect; Antigens; Apoptosis; Apoptotic; Biological; Breast; Cancer Model; Cancer Patient; Cells; Cessation of life; Clinic; Clinical Trials; Colorectal; Death Receptor 5; Disease remission; Dose; Ectopic Expression; Effector Cell; Exhibits; Genes; Genetic Engineering; Glioma; Goals; Hormonal; Human; Image; Immune; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; Ligands; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Measurable; Measurement; Mediating; Membrane; Mesothelioma; Modality; Monitor; Mus; Normal Cell; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Process; Prostate; Radiation; Radiation therapy; Recombinants; Reporter Genes; Resistance; Signal Transduction; Stimulus; Surface; T cell therapy; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; TNF gene; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; TP53 gene; Testing; Therapeutic; Time; Translating; Translations; Tumor Immunity; Whole-Body Irradiation; Work; Xenograft Model; base; cancer cell; cancer immunotherapy; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; chimeric antigen receptor; clinical application; cytotoxicity; factor A; immunogenic; improved; in vivo Model; innovation; irradiation; killings; mesothelin; neoplastic cell; non-invasive imaging; non-invasive monitor; novel; overexpression; pre-clinical; receptor; response; theranostics; tumor; tumor eradication; tumor xenograft

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 ectopic expression of therapeutic ligands (e.g. TRAIL) 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.

项目摘要 已证明癌细胞对肿瘤坏死因子α相关的凋亡刺激敏感 凋亡诱导配体（TRAIL），而正常细胞表现出非常小的反应。TRAIL被证明是 作为单一药剂具有活性并与某些化疗剂表现出协同活性，或 放疗，导致肿瘤明显消退或完全缓解。越来越多的证据表明 在活化的T淋巴细胞表面上表达的膜结合的TRAIL可以增强T细胞效应因子， 功能和增强T细胞杀肿瘤活性。通过基因工程改造原代T细胞的能力 在肿瘤免疫和癌症治疗方面具有很好的应用前景。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， 免疫原性或被免疫系统忽略。此外，治疗性配体（例如， TRAIL）可以有效地增加它们的杀肿瘤活性。肿瘤对基于TRAIL的肿瘤细胞致敏的新策略 免疫疗法和TRAIL抗性的调节正在开发中，其中一些可以转化为 诊所我们的中心主题和假设是，T细胞过度表达TRAIL导致了T细胞凋亡的增加。 肿瘤细胞凋亡和放射和/或化学疗法积极影响TRAIL介导肿瘤 T细胞过继免疫治疗期间的细胞凋亡，可用作增强T细胞免疫的协同方法 肿瘤靶向和效应子功能。