权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CCSG Supplement: Early-stage Surgeon Scientist Program (ESSP) - Chibawanye Ene

CCSG 增刊：早期外科医生科学家计划 (ESSP) - Chibawanye Ene

基本信息

批准号：
10748481
负责人：
Giulio Francesco Draetta
金额：
$ 20.25万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-28 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10748481
关键词：
Adult Aftercare Ants Attention Automobile Driving Biological Blood CD14 gene CD3 Antigens CD8-Positive T-Lymphocytes Cancer Center Cancer Center Support Grant Cell Communication Cell secretion Chemotherapy and/or radiation Circulation Clinical Clinical Trials Data Engineering Environment Evaluation Genes Glioblastoma Glioma Grant Granzyme High Prevalence Human Immune Immune checkpoint inhibitor Immune response Immunomodulators Immunosuppression Immunotherapeutic agent Immunotherapy Impairment In complete remission Infection Infiltration Interleukin-12 Knockout Mice Knowledge Link Long-Term Survivors MART-1 Tumor Antigen Macrophage Malignant Neoplasms Mediating Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Oncolytic viruses Operative Surgical Procedures Outcome Patient Selection Patients Phase I Clinical Trials Predisposition Primary Brain Neoplasms Recurrence Research Personnel Resistance Scientist Standard Model Surgeon Survival Rate Survivors T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Time Tumor Antigens Vaccines Viral anti-tumor immune response cell mediated immune response chimeric antigen receptor conditional knockout cytokine effector T cell experience immune health immunosuppressed improved interest monocyte mouse model new therapeutic target novel strategies oncolytic virotherapy pre-clinical programmed cell death ligand 1 programs response synergism tumor

项目摘要

SUMMARY AND ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-100. Glioblastoma (GBM), the most common primary brain tumor in adults has a median survival of only 14.6months despite aggressive surgery, radiation and chemotherapy. This outcome has not changed in the past 20 years as many of the newer targeted therapies and even immunotherapies, which have been highly effective in other cancers, have proven ineffective in GBM. Delta-24RGD oncolytic virus is a form of immunotherapy that has shown efficacy with complete responses in 15% of GBM patients (or long-term survivors) as part of a clinical trial performed here at MD Anderson Cancer Center. Short term survivors, however, showed no clinical response following Delta-24RGD oncolytic virus treatment. Virally induced anti-glioma CD8+ T-cell responses were observed in some long-term survivors following treatment, indicating that Delta-24RGD elicits an ant-tumor immune response in GBM. It is unclear why short-term survivors lacked an anti-tumor immune response. Recent studies have shown that patients with GBM have some of the highest levels of circulating immunosuppressive myeloid cells, particularly PD-L1+ myeloid-derived suppressor cells (MDSCs), and that the levels of these PD- L1+ immunosuppressive myeloid cells correlate with poor outcomes in GBM patients receiving immunotherapies. Our preliminary data showed that Delta-24RGD oncolytic virus long term survivors have higher levels of the potent polyfunctional and anti-tumor T-cell sub-population in circulation after treatment. It remains unclear whether immunosuppressive PD-L1+ MDSCs modulate the levels of polyfunctional T-cells resulting in a lack of expansion following Delta-24RGD oncolytic virus treatment especially in short-term survivors. We hypothesize that circulating immunosuppressive myeloid cells inhibit circulating T-cell activation and polyfunctionality resulting in resistance of GBM patients to Delta-24RGD oncolytic virus. To assess our hypothesis, we will compare the levels of PD-L1+ MDSCs in Delta-24RGD responders to non-responders. In a mouse GBM model that re-capitulates the high levels of PD-L1+ MDSCs in circulation, we will evaluate whether Delta-24RGD oncolytic virus is more effective following selectively depletion of circulating PD-L1+ MDSCs. Finally, we propose a therapeutic strategy to overcome systemic myeloid mediated immunosuppression by administering genetically modified macrophages expressing T-cell activating cytokine IL-12 prior to Delta-24RGD oncolytic virus treatment.

内容和摘要本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 21-100. 胶质母细胞瘤（GBM）是成人最常见的原发性脑肿瘤，中位生存期仅为14.6个月尽管进行了积极的手术放疗和化疗这一结果在过去20年里没有改变，许多较新的靶向治疗，甚至免疫治疗，在其他疾病中非常有效，癌症，已经证明对GBM无效。Delta-24 RGD溶瘤病毒是一种免疫疗法，作为临床试验的一部分，在15%的GBM患者（或长期存活者）中显示出完全缓解的疗效在MD安德森癌症中心进行。然而，短期存活者没有表现出临床反应在Delta-24 RGD溶瘤病毒处理后。病毒诱导的抗神经胶质瘤CD 8 + T细胞应答是在治疗后的一些长期存活者中观察到，表明Delta-24 RGD具有抗肿瘤作用， GBM中的免疫应答。目前尚不清楚为什么短期存活者缺乏抗肿瘤免疫反应。最近研究表明，GBM患者的循环免疫抑制水平最高，骨髓细胞，特别是PD-L1+骨髓来源的抑制细胞（MDSC），以及这些PD-L1的水平， L1+免疫抑制性骨髓细胞与接受免疫治疗的GBM患者的不良结局相关。我们的初步数据显示，Delta-24 RGD溶瘤病毒的长期存活者具有更高水平的治疗后循环中有效的多功能和抗肿瘤T细胞亚群。目前还不清楚免疫抑制性PD-L1+ MDSC是否调节多功能T细胞的水平，导致缺乏免疫抑制性T细胞，在Delta-24 RGD溶瘤病毒治疗后的扩增，特别是在短期存活者中。我们假设循环免疫抑制性骨髓细胞抑制循环T细胞活化和多功能性导致GBM患者对Delta-24 RGD溶瘤病毒的抗性。为了评估我们的假设，我们将比较Delta-24 RGD应答者与无应答者中的PD-L1+ MDSC水平。在小鼠GBM模型中，我们将评估Delta-24 RGD是否能在循环中重新发现高水平的PD-L1+ MDSC，溶瘤病毒在选择性消耗循环PD-L1+ MDSC后更有效。最后提出通过遗传给药克服系统性骨髓介导的免疫抑制的治疗策略在Delta-24 RGD溶瘤病毒之前表达T细胞活化细胞因子IL-12的修饰的巨噬细胞治疗