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

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

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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.

摘要和摘要该申请是为了响应特殊利益通知（NOSI）而提交 21-100。胶质母细胞瘤（GBM），成人最常见的原发性脑肿瘤的中位生存期仅为14.6个月尽管进行了侵略性手术，放射线和化学疗法。在过去的20年中，这种结果并没有改变许多较新的有针对性疗法甚至免疫疗法，这些疗法在其他方面非常有效癌症在GBM中被证明无效。 Delta-24RGD溶瘤病毒是一种免疫疗法的一种形式作为临床试验的一部分，在15％的GBM患者（或长期幸存者）中表现出了有效性在MD Anderson癌症中心在这里演出。然而，短期幸存者没有临床反应 Delta-24RGD癌性病毒治疗后。病毒诱导的抗脱脂瘤CD8+ T细胞反应为在治疗后在一些长期幸存者中观察到 GBM的免疫反应。目前尚不清楚为什么短期幸存者缺乏抗肿瘤免疫反应。最近的研究表明，GBM患者具有最高水平的循环免疫抑制作用髓样细胞，尤其是PD-L1+髓样衍生的抑制细胞（MDSC），并且这些PD-的水平 L1+免疫抑制性髓样细胞与接受免疫疗法的GBM患者的结局不佳。我们的初步数据表明，Delta-24RGD溶瘤病毒长期幸存者具有更高的水平治疗后循环中有效的多功能和抗肿瘤T细胞亚群。目前尚不清楚免疫抑制PD-L1+ MDSC是否调节多功能T细胞的水平，导致缺乏 Delta-24RGD肿瘤病毒治疗后，特别是在短期幸存者中的扩张。我们假设循环的免疫抑制髓样细胞抑制了循环的T细胞激活和多功能性导致GBM患者对Delta-24RGD溶瘤病毒的耐药性。为了评估我们的假设，我们将比较Delta-24RGD响应者中的PD-L1+ MDSC的水平。在鼠标GBM模型中这重新计算了高水平的PD-L1+ MDSC在循环中，我们将评估Delta-24RGD是否在选择性耗尽循环PD-L1+ MDSC之后，溶瘤病毒更有效。最后，我们建议通过遗传施用的治疗策略来克服全身性髓样介导的免疫抑制在Delta-24RGD溶瘤病毒之前表达T细胞活化细胞因子IL-12的改良巨噬细胞治疗。