Explore Gamma delta T cell-based glioblastoma therapies

探索基于 Gamma delta T 细胞的胶质母细胞瘤疗法

• 批准号: 10829731
• 负责人: Meenhard F Herlyn
• 金额: $ 15.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-13 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10829731
• 关键词: Adult; Affect; Brain Neoplasms; CAR T cell therapy; Cell Therapy; Cells; Cellular immunotherapy; Collaborations; Combined Modality Therapy; Data; Development; Down-Regulation; Glioblastoma; Immune; Immunosuppression; Immunotherapy; Investigational Therapies; Macrophage; Malignant - descriptor; Melanoma Cell; Modeling; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Natural Immunity; Normal Cell; Primary Brain Neoplasms; Refractory; Solid Neoplasm; Source; System; T cell infiltration; T cell therapy; T-Lymphocyte; TNFRSF10B gene; Testing; Toxic effect; Tumor Immunity; Xenograft Model; adaptive immunity; beta-2 Microglobulin; chimeric antigen receptor; immune checkpoint blockade; interest; mouse model; neoplastic cell; novel; pre-clinical; response; tumor; tumor microenvironment; tumor-immune system interactions; γδ T cells

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Our long-term objective is to develop highly effective cellular immunotherapies for solid tumors. In response to this NOSI, we will start a new collaboration with Dr. Yi Fan to develop chimeric antigen receptor (CAR)-T cell therapy for glioblastoma (GBM). GBM is the most common and most aggressive malignant primary brain tumor in adults, with a median overall survival of about 14-18 months. GBM tumors are also generally refractory to T cell-based immunotherapies, largely due to the immune-hostile tumor microenvironment (TME) that inhibits T cell activity. Tumor-associated myeloid cells, including myeloid-derived suppressor cells (MDSCs) and macrophages, are the major source for GBM immunosuppression, but there are currently no effective approaches to eradicate these immunosuppressive cells. Adoptive T cell transfer has to date focused mainly on αβT cell therapy. Unlike αβT cells, γδT cells manifest the features of both innate and adaptive immunity. Downregulation or loss of HLA class I or β2 microglobulin which makes tumor cells undetectable to αβT cells, is unlikely to affect γδT cell recognition. For proof-of-concept, we have developed novel CARs targeting Death Receptor 5 (DR5). DR5 is highly expressed by GBM cells and MDSCs, but not by most normal cells. Our preliminary data demonstrated that DR5-CARs may significantly inhibit both MDSCs and DR5-expressing melanoma cells with little toxicity to normal cells in xenograft models. Here, we will develop a fully murine DR5-targeting CAR T system that can be used in treating syngeneic mouse GBM models with an intact immune TME. We hypothesize that DR5-CAR-γδT cells modulate TME and have robust anti-tumor activity in GBM. In Aim 1, we will evaluate the effects of DR5-CAR T cells on tumor immunity in preclinical syngeneic mouse GBM models. In Aim 2, we will test experimental therapy that combines DR5- CAR T cells with PAK4 inhibition (to enhance T cell infiltration) and/or immune checkpoint blockade (to increase T cell activity) to treat GBM in preclinical mouse models. We expect that CAR T cells targeting DR5 may eliminate MDSCs and tumor cells in GBM and reverse tumor immunosuppression in the TME to allow host immune cells to function properly. Successful completion of this project may lead to development of a new CAR T cell immunotherapy for brain tumor.

该申请是根据特殊利益通知（NOSI）提交的 被确定为非CA-23-045。我们的长期目标是开发高效的细胞 实体瘤的免疫疗法。为了回应这种NOSI，我们将开始新的合作 与Yi Fan博士一起开发用于胶质母细胞瘤的嵌合抗原受体（CAR）-T细胞疗法 （GBM）。 GBM是成年人中最常见，最具侵略性的恶性原发性脑肿瘤， 总体生存中位数约为14-18个月。 GBM肿瘤通常也是难治性的 对于基于T细胞的免疫疗法，主要是由于免疫抑制肿瘤微环境 （TME）抑制T细胞活性。肿瘤相关的髓样细胞，包括髓样衍生的 抑制细胞（MDSC）和巨噬细胞是GBM的主要来源 免疫抑制，但目前尚无有效的方法来放射线 免疫抑制细胞。迄今为止，收养T细胞转移主要集中在αβT细胞上 治疗。与αβT细胞不同，γδT细胞表现出先天和适应性免疫组织化学的特征。 HLA I类或β2微球蛋白的下调或丧失，使肿瘤细胞无法检测到 对于αβT细胞，不太可能影响γδT细胞识别。为了证明概念，我们已经开发了 针对死亡受体5（DR5）的新型汽车。 DR5由GBM细胞高度表达 MDSC，但不是大多数正常细胞。我们的初步数据表明DR5卡可能 显着抑制MDSC和表达DR5的黑色素瘤细胞，毒性很小至正常 异种移植模型中的细胞。在这里，我们将开发一个完全鼠DR5的靶向汽车T系统 可用于使用完整的免疫TME处理合成小鼠GBM模型。我们 假设DR5-CAR-γδT细胞调节TME，并在GBM中具有强大的抗肿瘤活性。 在AIM 1中，我们将评估DR5-CART细胞对临床前肿瘤免疫学的影响 合成小鼠GBM模型。在AIM 2中，我们将测试结合DR5-的实验疗法 具有PAK4抑制（增强T细胞浸润）和/或免疫检查点的CART细胞 封锁（增加T细胞活性）以治疗临床前小鼠模型中的GBM。我们期望这一点 靶向DR5的CART细胞可以消除GBM中的MDSC和肿瘤细胞和反向肿瘤 TME中的免疫抑制使宿主免疫细胞能够正常运行。成功的 该项目的完成可能会导致开发新的汽车T细胞免疫疗法 脑肿瘤。