Oncolytic Polovirus, Immunotoxin, and Checkpoint Inhibitor Therapy of Gliomas

 描述(申请人提供)：本杰出研究者奖申请中描述的该项目的中心假设是，区域性肿瘤靶向细胞毒疗法，如溶瘤脊髓灰质炎病毒(PVS-RIPO)和D2C7 PE38免疫毒素(D2C7-IT)，不仅特异性地靶向并摧毁肿瘤细胞，而且在此过程中引发免疫事件，促进原位疫苗效应，该效应可以通过免疫检查点阻断来放大，以产生长期的系统免疫反应，有效地消除复发和播散性的多形性胶质母细胞瘤(GBM)。最终，这两种药物可以一起使用，提供两种不同的抗原靶点和细胞毒性机制，以及免疫检查点阻断。在赠款的最初几年，携带人类脊髓灰质炎病毒基因的转基因小鼠将允许3个已转人脊髓灰质炎病毒受体基因的星形细胞小鼠肿瘤细胞原位生长。由此产生的肿瘤将被PVS-RIPO治疗，免疫反应的性质和机制将被表征。之后，星形细胞动物肿瘤将在原位生长，用PVS-Ripo治疗，然后用抗CTLA-4和PD1检查点抑制剂单独或一起治疗。D2C7免疫毒素将在3个星形细胞小鼠肿瘤模型中进行类似的研究，这些模型已经导入了小鼠版本的人表皮生长因子受体基因，该基因包含与D2C7-IT反应的小鼠表位。对D2C7 EGFR表位转基因的原位小鼠星形细胞肿瘤进行的类似系列研究将用D2C7-IT以及单独和联合使用检查点抑制剂抗CTLA-4和PD1进行治疗。使用检查点抑制剂，将深入研究治疗前后的免疫反应。在这些动物研究之后，将在GBM患者中进行类似的一系列人类临床试验，分别使用PVS-Ripo或D2C7-IT以及检查点抑制剂抗CTLA-4和PD1进行治疗，两者单独并最终一起使用。我相信这些研究的结果将代表着GBM治疗模式的转变，从而显著提高高生活质量和总存活率。

 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.