Oncolytic Polovirus, Immunotoxin, and Checkpoint Inhibitor Therapy of Gliomas

 描述（申请人提供）：该杰出研究者奖申请中描述的项目的中心假设是，区域肿瘤靶向细胞毒性疗法，如溶瘤脊髓灰质炎病毒，（PVS-RIPO）和D2 C7 PE 38免疫毒素（D2 C7-IT），不仅特异性靶向和破坏肿瘤细胞，而且在此过程中启动促进原位疫苗效应的免疫事件，其可以通过免疫检查点阻断而被放大，以产生长期的系统性免疫应答，该免疫应答有效地消除复发性和播散性多形性胶质母细胞瘤细胞（GBM）。最终，两种试剂可以一起使用，提供两种不同的抗原靶标和细胞毒性机制沿着免疫检查点阻断。在拨款的最初几年，携带人脊髓灰质炎病毒基因的转基因小鼠将允许3个已转染人脊髓灰质炎病毒受体基因的星形胶质细胞小鼠肿瘤细胞原位生长。将用PVS-RIPO治疗所得肿瘤，并表征免疫应答的性质和机制。之后，星形胶质细胞动物肿瘤将原位生长，用PVS-RIPO处理，然后用抗CTLA-4和PD 1检查点抑制剂单独和一起处理。将在3种星形胶质细胞鼠肿瘤模型中用D2 C7免疫毒素进行类似的一组研究，所述模型已用鼠形式的人表皮生长因子受体基因转染，所述人表皮生长因子受体基因含有与D2 C7-IT反应的鼠表位。将用D2 C7-IT治疗用D2 C7 EGFR表位转染的原位鼠星形胶质细胞肿瘤的类似系列研究，以及单独和与检查点抑制剂抗CTLA-4和PD 1一起。在检查点抑制剂治疗前后，将深入表征免疫应答。在这些动物研究之后，将在GBM患者中进行一系列类似的人体临床试验，分别使用PVS-RIPO或D2 C7-IT以及检查点抑制剂抗CTLA-4和PD 1进行治疗，并最终一起进行治疗。我相信这些研究的结果将代表GBM治疗的范式转变，导致高生活质量和总体生存率的显着提高。

 DESCRIPTION (provided by applicant): The central hypothesis of the project described in this Outstanding Investigator Award application is that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus (PVS-RIPO) and the D2C7 PE38 immunotoxin (D2C7-IT), not only specifically target and destroy tumor cells, but in the process initiate immune events that promote an in situ vaccine effect, which can be amplified by immune checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated glioblastoma multiforme cells (GBM). Ultimately, both agents may be used together providing two different antigenic targets and cytotoxicity mechanisms along with immune checkpoint blockade. In the initial years of the grant, transgenic mice carrying the human poliovirus gene will allow orthotopic growth of 3 astrocytic murine tumor cells that have been transfected with the human poliovirus receptor gene. The resultant tumors will be treated with PVS-RIPO and the nature and mechanism of the immune response will be characterized. Following that, the astrocytic animal tumors will be grown orthotopically, treated with PVS-RIPO, and then treated with anti-CTLA-4 and PD1 checkpoint inhibitors, both individually and together. A similar set of studies will be carried out with the D2C7 immunotoxin in 3 astrocytic murine tumor models that have been transfected with the murine version of the human epidermal growth factor receptor gene, which contains the murine epitope reactive with the D2C7-IT. A similar series of studies with orthotopic murine astrocytic tumors transfected with the D2C7 EGFR epitope will be treated with D2C7-IT, and individually and together, with the checkpoint inhibitors anti-CTLA-4 and PD1. The immune response will be characterized in depth, before and after treatment, with the checkpoint inhibitors. Following these animal studies, a similar series of human clinical trials in GBM patients will be carried out with treatment with either PVS-RIPO or D2C7-IT and the checkpoint inhibitors anti-CTLA-4 and PD1, both individually, and ultimately together. I believe the outcome of these studies will represent paradigm shifts in GBM treatment resulting in significant increases in high quality of life and overall survival.