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.

本申请是为了响应特别利益通知 (NOSI) 而提交的 我们的长期目标是开发高效的细胞。 针对实体瘤的免疫疗法，我们将开始一项新的合作。 与范毅博士合作开发针对胶质母细胞瘤的嵌合抗原受体（CAR）-T细胞疗法 (GBM) 是成人中最常见和最具侵袭性的恶性原发性脑肿瘤。 GBM 肿瘤的中位总生存期约为 14-18 个月，通常也是难治性的。 基于 T 细胞的免疫疗法，很大程度上是由于免疫敌对的肿瘤微环境 (TME) 抑制肿瘤相关的骨髓细胞，包括骨髓来源的细胞。 抑制细胞 (MDSC) 和巨噬细胞是 GBM 的主要来源 免疫抑制，但目前还没有有效的方法来根除这些 迄今为止，过继性 T 细胞移植主要集中在 αβT 细胞上。 与αβT细胞不同，γδT细胞表现出先天性免疫和适应性免疫的特征。 HLA I 类或 β2 微球蛋白下调或缺失，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。 靶向死亡受体 5 (DR5) 的新型 CAR 在 GBM 细胞中高度表达。 MDSC，但不是大多数正常细胞。我们的初步数据表明 DR5-CAR 可能。 显着抑制 MDSC 和表达 DR5 的黑色素瘤细胞，对正常细胞毒性很小 在这里，我们将开发一种完全针对小鼠 DR5 的 CAR T 系统。 可用于治疗具有完整免疫 TME 的同基因小鼠 GBM 模型。 DR5-CAR-γδT 细胞调节 TME，并在 GBM 中具有强大的抗肿瘤活性。 在目标1中，我们将在临床前评估DR5-CAR T细胞对肿瘤免疫的影响 在目标 2 中，我们将测试结合 DR5- 的实验疗法。 具有 PAK4 抑制（以增强 T 细胞浸润）和/或免疫检查点的 CAR T 细胞 我们预计，在临床前小鼠模型中，通过阻断（以增加 T 细胞活性）来治疗 GBM。 靶向DR5的CAR-T细胞可以消除GBM中的MDSC和肿瘤细胞并逆转肿瘤 TME 中的免疫抑制使宿主免疫细胞成功发挥作用。 该项目的完成可能会导致开发一种新的 CAR T 细胞免疫疗法 脑肿瘤。