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

• 批准号: 10221622
• 负责人: DARELL D BIGNER
• 金额: $ 91.95万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10221622
• 关键词: Aftercare; Animals; Astrocytes; Astrocytoma; Award; Bacterial Toxins; Cells; Clinical Trials; Cytotoxic Chemotherapy; EGFR gene; Epidermal Growth Factor Receptor; Epitopes; Event; Genes; Glioblastoma; Glioma; Grant; Growth; Human; Human poliovirus; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunotoxins; Individual; Malignant neoplasm of brain; Modeling; Mus; Nature; Oncolytic; Oncolytic poliovirus; Outcome Study; Patients; Process; Quality of life; Receptor Gene; Recurrence; Research Personnel; Series; Transgenic Mice; anti-CTLA4; checkpoint therapy; cytotoxicity; immune checkpoint blockade; improved; in situ vaccine; neoplastic cell; programmed cell death protein 1; public health relevance; tumor

 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.

 描述（由申请人提供）：本杰出研究者奖申请中描述的项目的中心假设是，区域性肿瘤靶向细胞毒性疗法，例如溶瘤脊髓灰质炎病毒（PVS-RIPO）和D2C7 PE38免疫毒素（D2C7-IT），不仅特异性靶向并破坏肿瘤细胞，但在此过程中启动促进原位疫苗效应的免疫事件，该效应可以通过免疫检查点阻断来放大，从而产生长期效果最终，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。人脊髓灰质炎病毒基因将允许已转染人脊髓灰质炎病毒受体基因的3个星形细胞鼠肿瘤细胞原位生长。所得肿瘤将被治疗。 PVS-RIPO 以及免疫反应的性质和机制将得到表征，星形细胞动物肿瘤将原位生长，用 PVS-RIPO 处理，然后用抗 CTLA-4 和 PD1 检查点抑制剂单独处理。并将在 3 个已转染鼠类人表皮生长因子受体基因的星形胶质细胞肿瘤模型中使用 D2C7 免疫毒素进行一组类似的研究，含有与 D2C7-IT 反应的小鼠表位的类似系列研究将用 D2C7-IT 单独或与抗 CTLA-4 检查点抑制剂一起治疗转染 D2C7 EGFR 表位的原位小鼠星形细胞肿瘤。在这些动物研究之后，将在 GBM 中进行一系列类似的人体临床试验，以深入表征治疗前后的免疫反应。患者将接受 PVS-RIPO 或 D2C7-IT 以及检查点抑制剂抗 CTLA-4 和 PD1 的单独治疗，并最终联合治疗，我相信这些研究的结果将代表 GBM 治疗的范式转变。显着提高生活质量和总体生存率。

项目成果

Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models.

重组溶瘤脊髓灰质炎病毒 (PVSRIPO) 具有强大的细胞毒性和先天炎症作用，可介导人类乳腺癌和前列腺癌异种移植模型的治疗。

• 发表时间: 2016-11-29
• 作者: Holl, Eda K;Brown, Michael C;Boczkowski, David;McNamara, Megan A;George, Daniel J;Bigner, Darell D;Gromeier, Matthias;Nair, Smita K
• 通讯作者: Nair, Smita K

EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery.

EGFR/EGFRvIII 靶向免疫毒素疗法通过对流增强递送治疗胶质母细胞瘤。

• 发表时间: 2016
• 作者: Bao, Xuhui;Pastan, Ira;Bigner, Darell D;Chandramohan, Vidyalakshmi
• 通讯作者: Chandramohan, Vidyalakshmi

Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs.

使用重组脊髓灰质炎病毒进行癌症免疫治疗可诱导树突状细胞和肿瘤抗原特异性 CTL 的 IFN 主导激活。

• 发表时间: 2017-09-20
• 影响因子: 17.1
• 作者: Brown, Michael C;Holl, Eda K;Boczkowski, David;Dobrikova, Elena;Mosaheb, Mubeen;Chandramohan, Vidya;Bigner, Darell D;Gromeier, Matthias;Nair, Smita K
• 通讯作者: Nair, Smita K

Recurrent Glioblastoma Treated with Recombinant Poliovirus.

用重组脊髓灰质炎病毒治疗复发性胶质母细胞瘤。

• 发表时间: 2018-07-12
• 作者: Desjardins, Annick;Gromeier, Matthias;Herndon 2nd, James E;Beaubier, Nike;Bolognesi, Dani P;Friedman, Allan H;Friedman, Henry S;McSherry, Frances;Muscat, Andrea M;Nair, Smita;Peters, Katherine B;Randazzo, Dina;Sampson, John H;Vlahovic, Gordan
• 通讯作者: Vlahovic, Gordan

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

极低的突变负荷是对癌症免疫治疗有反应的发炎性复发性胶质母细胞瘤的一个特征。

• 发表时间: 2021
• 影响因子: 16.6
• 作者: Gromeier, Matthias;Brown, Michael C;Zhang, Gao;Lin, Xiang;Chen, Yeqing;Wei, Zhi;Beaubier, Nike;Yan, Hai;He, Yiping;Desjardins, Annick;Herndon 2nd, James E;Varn, Frederick S;Verhaak, Roel G;Zhao, Junfei;Bolognesi, Dani P;Friedman, Allan H;F
• 通讯作者: F