Oncolytic Polovirus, Immunotoxin, and Checkpoint Inhibitor Therapy of Gliomas

胶质瘤的溶瘤脊髓灰质炎病毒、免疫毒素和检查点抑制剂治疗

基本信息

批准号：
9751789
负责人：
DARELL D BIGNER
金额：
$ 87.93万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2022-07-31
项目状态：
已结题

项目摘要

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.

DESCRIPTION (provided by application): 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 immuno events that promote an in situ vaccine effect, which can通过免疫检查点阻滞剂进行扩增，以产生长期的全身免疫反应，从而有效消除复发和传播的胶质母细胞瘤多形细胞（GBM）。最终，两种药物都可以一起使用，从而提供两个不同的抗原靶标和细胞毒性机制以及免疫切除点阻滞。在该赠款的最初几年中，携带人脊髓灰质炎病毒基因的转基因小鼠将允许3个已被人脊髓灰质炎病毒受体基因转染的3种星形细胞鼠肿瘤细胞的原位生长。所得的肿瘤将用PVS-RIPO处理，并将表征免疫增强响应的性质和机制。随后，星形胶质细胞肿瘤将以原位生长，用PVS-RIPO处理，然后单独和一起用抗CTLA-4和PD1检查点抑制剂进行治疗。在3种星形细胞鼠肿瘤模型中，将使用D2C7免疫毒素进行类似的研究，这些模型已与人类表皮生长因子受体基因的鼠版本进行了翻译，其中包含带有D2C7-IT的鼠表位反应性。对用D2C7 EGFR表位翻译的原位鼠星形肿瘤进行的类似的研究将用D2C7-IT处理，并与检查点抑制剂抗CTLA-4和PD1一起进行处理。免疫反应将在处理点抑制剂前后深入表征。在这些动物研究之后，将通过PVS-RIPO或D2C7-IT进行类似的GBM患者进行类似的人类临床试验，以及单独的抗CTLA-4和PD1检查点抑制剂抗CTLA-4和PD1。我认为这些研究的结果将代表GBM治疗的范式转移，从而导致高质量的生活质量和整体生存率显着增加。