Imaging the efficacy of TRAIL-enhanced cancer immunotherapy

项目总结 肿瘤细胞对肿瘤坏死因子α相关的凋亡刺激很敏感 凋亡诱导配体(TRAIL)，而正常细胞反应很小。踪迹被证明是 作为单一药物有效，并与某些化疗药物或 放射治疗，导致肿瘤显著消退或完全缓解。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能增强T细胞效应 功能和增强T细胞杀瘤活性。对初级T细胞进行基因工程的能力创造了新的 以及在肿瘤免疫和癌症治疗方面非常有希望的前景。T细胞在体内的转导 编码嵌合抗原受体的基因使T细胞能够识别 免疫原性的或被免疫系统忽略的。此外，治疗性配体的异位表达(如 TRAIL)可以有效地增强其杀瘤活性。肿瘤对TRAIL增敏的新策略 免疫疗法和TRAIL耐药的调节正在开发中，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会导致 肿瘤细胞凋亡与放射和/或化疗对TRAIL介导的肿瘤的积极影响 T细胞过继免疫治疗中的细胞凋亡可作为增强T细胞的协同方法 肿瘤靶向和效应器功能。

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.