Image-guided TRAIL-enhanced CAR T-cell 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，基因工程表达的 T细胞的治疗性配体(如TRAIL)可以有效地增强其杀瘤活性。新的战略 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 还有一些可以被翻译到诊所。我们的中心主题和假设是T-TRAIL过度表达 细胞导致肿瘤细胞的凋亡增加，放射和/或化疗对此有积极的影响 T细胞过继免疫治疗中TRAIL介导的肿瘤细胞凋亡及其协同作用 增强T细胞肿瘤靶向性和效应器功能的途径。 在这项应用中，我们建议开发和测试一种新的治疗方法来增强肿瘤细胞的凋亡。 嵌合抗原过表达TRAIL诱导PSMA异质性前列腺癌模型 受体(CAR)-移植的PSMA特异性T细胞。我们将评估膜结合型和分泌型的效果 PSMA特异性T细胞表达的TRAIL形式对其杀伤PSMA阳性和阴性靶的能力的影响。 我们将确定放化疗是否诱导耐TRAIL的肿瘤细胞“敏化” 与增强的T细胞杀瘤功能相关。最终，我们将评估其可行性和敏感性。 用于监测PSMA特异性T细胞活化和TRAIL治疗有效载荷的PET成像 肿瘤。这些过程将使用多报告基因和通过评估T-T的常规成像来监测。 细胞肿瘤的靶向和激活以及肿瘤的反应。 我们的建议补充了MSK和其他癌症中心正在进行的临床研究，探索了新的 旨在增强T细胞效应器功能和改善治疗反应的策略。结果将会是 为前列腺癌患者的临床应用提供临床前支持和理据 其他接受转基因T细胞免疫治疗的癌症。 好了！

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. !