Explore Gamma delta T cell-based glioblastoma therapies

本申请是对特别利益通知(NOSI)的回应 标识为NOT-CA-23-045。我们的长期目标是开发高效的细胞 实体肿瘤的免疫疗法。作为对此的回应，我们将开始一项新的合作 与易帆博士合作开发嵌合抗原受体(CAR)-T细胞疗法治疗胶质母细胞瘤 (GBM)。基底节细胞瘤是成人最常见、最具侵袭性的恶性原发脑瘤， 中位总生存期约14-18个月。基底膜肿瘤通常也是难治性的。 以T细胞为基础的免疫治疗，很大程度上是由于免疫敌对的肿瘤微环境 (TME)抑制T细胞活性。肿瘤相关的髓系细胞，包括髓系细胞 抑制细胞(MDSCs)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 免疫抑制细胞。迄今为止，过继T细胞转移主要集中在αβT细胞上 心理治疗。与αβT细胞不同，γδT细胞同时具有先天免疫和获得性免疫的特点。 HLAI类或β2微球蛋白下调或丢失，使肿瘤细胞无法检测到 对αβT细胞来说，不太可能影响γδT细胞的识别。对于概念验证，我们开发了 以死亡受体5(DR5)为靶点的新型汽车。DR5在GBM细胞中高表达， MDSCs，但不是大多数正常细胞。我们的初步数据表明，DR5-CARS可能 显著抑制MDSCs和DR5表达的黑色素瘤细胞，对正常细胞毒性很小 异种移植模型中的细胞。在这里，我们将开发一种完全以小鼠DR5为靶点的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。我们 假设DR5-CAR-γδT细胞调节TME，并在基底膜中具有强大的抗肿瘤活性。 在目标1中，我们将评估DR5-CART细胞对临床前肿瘤免疫的影响。 同基因小鼠肾小球基底膜模型。在目标2中，我们将测试结合DR5- 具有PAK4抑制(以增强T细胞渗透)和/或免疫检查点的CART细胞 阻断(增加T细胞活性)治疗临床前小鼠模型中的GBM。我们期待着 靶向DR5的CART细胞可清除基底膜中的MDSCs和肿瘤细胞并逆转肿瘤 TME中的免疫抑制，以允许宿主免疫细胞正常运行。成功 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 脑瘤。

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.