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Design of a Novel Nanocarrier Technology to Drug-Load CAR T cells

用于载药 CAR T 细胞的新型纳米载体技术的设计

基本信息

批准号：
10734365
负责人：
David Akhavan
金额：
$ 57.44万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734365
关键词：
Address Adjuvant Adoptive Cell Transfers Adult Affect Antibody Specificity Biochemical Brain Neoplasms Cell Survival Cell physiology Cells Cessation of life Chimeric Proteins Clinical Clinical Trials Cytolysis Data Disease Doctor of Philosophy Dominant-Negative Mutation Drug Utilization Drug toxicity Drug vehicle Epidermal Growth Factor Receptor Esters Evaluation Excision FDA approved Gingiva Glioblastoma Goals Growth Factor Inhibition Growth Factor Receptors Half-Life Hematologic Neoplasms Hemorrhage Histiocytosis Immune In Vitro Intracranial Hemorrhages Kansas Label Laboratories Life Macrophage Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of prostate Mediating Modeling Mus Nanotechnology Oncogenic Patients Penetration Peptides Pharmaceutical Preparations Phosphotransferases Polymers Pre-Clinical Model Principal Investigator Production Recurrence Reporting Research Resistance Route Solid Neoplasm T cell therapy T-Lymphocyte Technology Testing Therapeutic Toxic effect Transforming Growth Factors Universities Up-Regulation cell killing chemoradiation chimeric antigen receptor chimeric antigen receptor T cells comparative efficacy cytokine design dosage drug candidate experience immunotoxicity improved in vivo inhibitor interest invention kinase inhibitor manufacture nanocarrier nanotechnology platform new therapeutic target novel novel therapeutics overexpression pre-clinical programmed cell death ligand 1 receptor research clinical testing response small molecule small molecule inhibitor success systemic toxicity targeted treatment technology platform therapeutic target tumor tumor eradication tumor microenvironment tumor specificity uptake

项目摘要

Project summary: Current treatment for Glioblastoma Multiforme (GBM), the most common malignant brain tumor in adults, involves maximal safe resection, followed by adjuvant chemoradiation. Although this treatment is life prolonging, it is never curative. Five year survival is less than 7 %1 and improved therapies are urgently needed. In this proposal, we aim to develop a new targeted therapy with reduced toxicity and increased efficacy for GBM patients by leveraging nanotechnology discoveries in our laboratory to improve adoptive cell therapy. Chimeric Antigen Receptor (CAR) T cells combine the cytolytic potency of a T cell with the tumor specificity of an antibody. Recent clinical trial experiences of CAR T cells in solid tumors have identified the immune-suppressive tumor microenvironment (TME) as a major barrier to clinical success2-4. One immune-suppressive endogenous negative regulator in GBM TME is TGFβ, which has been identified as barrier to CAR T tumor eradication. Small molecule inhibitors of the TGFβ receptor as well as TGFβ resistant CAR T cells have been developed and tested clinically, however they are limited due to systemic toxicity. Herein we propose developing a platform technology to drug-load CAR T cells with nanocarriers, thus enhancing the therapeutic window of CAR T cells, and addressing one of the major obstacles to CAR T cells in brain tumors.

项目概要：多形性胶质母细胞瘤（GBM）是成人最常见的恶性脑肿瘤，目前的治疗方法涉及最大程度的安全切除，然后进行辅助放化疗。虽然这种治疗可以延长生命，它从来没有治疗作用。五年生存率低于 7%1，迫切需要改进的治疗方法。在这个根据提案，我们的目标是开发一种新的靶向疗法，降低 GBM 患者的毒性并提高疗效通过利用我们实验室的纳米技术发现来改善过继细胞疗法。嵌合抗原受体 (CAR) T 细胞将 T 细胞的细胞溶解能力与抗体的肿瘤特异性相结合。最近的 CAR T细胞在实体瘤中的临床试验经验已确定免疫抑制性肿瘤微环境（TME）是临床成功的主要障碍2-4。一种内源性免疫抑制 GBM TME 中的负调节因子是 TGFβ，它已被确定为根除 CAR T 肿瘤的障碍。小的 TGFβ受体分子抑制剂以及TGFβ抗性CAR T细胞已被开发和测试但在临床上，它们由于全身毒性而受到限制。在此我们建议开发一种平台技术用纳米载体装载药物的CAR T细胞，从而增强CAR T细胞的治疗窗口，以及解决 CAR T 细胞治疗脑肿瘤的主要障碍之一。