CAR T platform to treat solid tumors

治疗实体瘤的CAR T平台

基本信息

批准号：
10551607
负责人：
Joana M Murad
金额：
$ 36.81万
依托单位：
CELDARA MEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10551607
关键词：
ARHGEF5 gene Adoptive Transfer Antigen Targeting Antigens Antitumor Response CAR T cell therapy Cause of Death Cell Surface Proteins Cell Therapy Cells Clinical Clinical Research Colon Diagnosis Dose Effectiveness Engineering Environment Future Hematologic Neoplasms Human Immune Immune system Immunoglobulins Immunosuppression Immunotherapy Impairment In Vitro Interferon Type II Interleukin-2 Investigation Kinetics Lead Leukocytes Liquid substance Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Metastatic Melanoma Modeling Mucin 1 protein Mus Myeloid Cells Natural Killer Cells Nature Ovarian Ovarian Clear Cell Tumor Patients Pharmaceutical Preparations Phase Psychological reinforcement Race Refractory Renal Cell Carcinoma Role Safety Schedule Site Solid Solid Neoplasm Specificity Surface System T-Lymphocyte Therapeutic Tissues Toxic effect Tumor Cell Line Tumor Immunity United States anti-tumor immune response base cancer cell cancer heterogeneity chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical development clinical translation cytokine cytotoxic cytotoxicity design effective therapy effector T cell exhaust experimental study immunogenic improved improved outcome in vivo inducible gene expression mortality neoplastic cell novel optimism perforin rat KIM-1 protein recruit success targeted treatment therapeutic development trafficking tumor tumor growth tumor microenvironment tumor-immune system interactions weapons

项目摘要

SUMMARY Cancer is one of the leading causes of death worldwide. Over the years, several treatment approaches have been developed. However, their effectiveness is severely limited by the heterogeneity of cancer cells. Thus, there is a constant need for development of therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient's immune system. Of note, renal cell carcinoma and ovarian cancer are considered immunogenic, or “hot” cancers, in that tumors are infiltrated with T cells. This provides optimism that the immune system can be harnessed to be a potent and durable weapon against these cancers. Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR T cells fail against solid tumors due to key obstacles presented by the tumor microenvironment (TME). We propose in this application to demonstrate proof-of-concept of a novel platform that can overcome the current barrier to CAR T cell therapy in solid tumors. Our strategy combines the specificity of anti-TIM1 CAR with modulation of the TME by a combination of two cytokines, leading to a shift from immunosuppressive to a cytotoxic environment. Our approach capitalizes on the recruitment and activation of a broad repertoire of endogenous innate and adaptive immune cells, including tumor-specific T cells. Super2 and IL-33 CAR T cells promote antitumor immunity in multiple murine solid tumor models and is impervious to antigen loss, highlighting its potential as a universal CAR T cell platform for treatment of solid tumors. Aims will include the following: Aim 1. Design and evaluate human constructs expressing anti-TIM1 CAR, Super2 and IL-33 in vitro. Aim 2. Demonstrate proof of concept (POC) of efficacy of a dual cytokine delivery by anti-TIM1 CAR T cells in a humanized model of Renal cell carcinoma (RCC).

概括癌症是全球死亡的主要原因之一。多年来，几种治疗方法有他们是开发的。但是，它们的有效性受到癌细胞的异质性的严重限制。那，始终需要发展理论方法的发展，例如利用和增强患者免疫系统正常容量的免疫疗法。值得注意的是，肾脏细胞癌和卵巢癌被认为是免疫原性或“热”癌症，因为肿瘤被浸润与T细胞。这使人们对可以利用免疫系统是潜力且耐用的乐观对这些癌症的武器。嵌合抗原受体（CAR）T细胞疗法已显示出针对血液学肿瘤的显着效率。然而， CAR T细胞因肿瘤微环境（TME）带来的关键障碍而导致的实体瘤失败。我们本应用程序中的提议证明了一个新型平台的概念证明，该平台可以克服当前实体瘤中汽车T细胞疗法的障碍。我们的策略将抗TIM1汽车的特异性与通过两种细胞因子的组合调节TME，导致从免疫抑制转变为A 细胞毒性环境。我们的方法利用了招募和激活的广泛曲目内源性的先天和适应性免疫小球，包括肿瘤特异性T细胞。 SUPER2和IL-33 CAR T细胞在多种鼠实体瘤模型中促进抗肿瘤免疫，并且不受抗原丧失的影响，突出显示它作为用于治疗实体瘤的通用汽车T细胞平台的潜力。目标将包括以下内容：目标 1。在体外设计和评估表达抗TIM1 CAR，SUPER2和IL-33的人类结构。目标2。展示抗TIM1 CAR T细胞双重细胞因子递送效率的概念证明（POC）肾细胞癌（RCC）的人源化模型。