Explore Gamma delta T cell-based glioblastoma therapies

本申请是根据特别利益通知（NOSI）提交的。 标识为NOT-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。为了应对这一NOSI，我们将开始新的合作， 与Yi Fan博士合作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是成人中最常见和最具侵袭性的恶性原发性脑肿瘤， 中位总生存期约为14-18个月。GBM肿瘤通常也是难治的 基于T细胞的免疫疗法，主要是由于免疫敌对的肿瘤微环境 (TME)抑制T细胞活性肿瘤相关骨髓细胞，包括骨髓来源的 抑制细胞（MDSC）和巨噬细胞是GBM的主要来源 免疫抑制，但目前还没有有效的方法来消除这些 免疫抑制细胞迄今为止，诱导性T细胞转移主要集中在αβT细胞 疗法与αβT细胞不同，γδT细胞表现出先天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，导致肿瘤细胞无法检测 对αβT细胞，不太可能影响γδT细胞的识别。为了验证概念，我们开发了 靶向死亡受体5（DR 5）的新型汽车。DR 5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，DR 5-汽车可能 显著抑制MDSC和表达DR 5的黑色素瘤细胞，对正常 异种移植模型中的细胞。在这里，我们将开发一种完全靶向小鼠DR 5的CAR T系统， 可用于治疗具有完整免疫TME的同系小鼠GBM模型。我们 假设DR 5-CAR-γδT细胞调节TME并在GBM中具有稳健抗肿瘤活性。 在目的1中，我们将在临床前评估DR 5-CAR嵌合T细胞对肿瘤免疫的作用。 同基因小鼠GBM模型。在目标2中，我们将测试结合DR 5- 具有PAK 4抑制（以增强T细胞浸润）和/或免疫检查点的CAR活化T细胞 阻断（以增加T细胞活性）以治疗临床前小鼠模型中的GBM。我们预计 靶向DR 5的CAR靶向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，以允许宿主免疫细胞正常发挥功能。成功 该项目的完成可能会导致开发一种新的CAR免疫球蛋白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.