Genetic Approaches to Optimize CAR T cells for Glioblastoma Therapy

优化 CAR T 细胞用于胶质母细胞瘤治疗的基因方法

• 批准号: 9790997
• 负责人: Irina V Balyasnikova
• 金额: $ 53.1万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790997
• 关键词: Address; Adoptive Transfer; Animal Model; Animals; Antibodies; Antigens; Antitumor Response; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CAR T cell therapy; CCL2 gene; Cells; Clinical Research; Complement; Data; Development; Engineering; Environment; Expression Profiling; Failure; Flow Cytometry; Frequencies; Future; Genetic Engineering; Glioblastoma; Glioma; Goals; Grant; Hematologic Neoplasms; Human; Image; Immune; Immunosuppressive Agents; Immunotherapy; In Vitro; Individual; Infiltration; Injections; Interleukin-15; Membrane; Modeling; Monitor; Mus; Normal tissue morphology; Outcome; Patients; Population; Primary Brain Neoplasms; Production; Proliferating; Receptor Cell; Regulatory T-Lymphocyte; Research; Site; Solid Neoplasm; Survival Analysis; Survival Rate; T cell therapy; T-Lymphocyte; Therapeutic; Time; Tissues; Transgenic Model; Transgenic Organisms; Treatment Failure; Tropism; Tumor Antigens; Tumor Burden; Tumor Escape; Variant; Xenograft Model; Xenograft procedure; base; chemokine; chemokine receptor; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytotoxic; cytotoxicity; engineered T cells; genetic approach; improved; in vivo; novel therapeutics; overexpression; pre-clinical; prevent; receptor; response; tool; trafficking; tumor; tumor microenvironment; virtual

Glioblastoma (GBM), the most frequently occurring and aggressive primary brain tumor, remains virtually incurable. Thus, there is an urgent need to develop new therapies. Genetically modified T cells expressing chimeric antigen receptors (CARs) have the potential to serve as a unique cytotoxic tool to specifically target GBM. CAR T cell therapy has been successful for hematological malignancies, but multiple challenges posed by the brain tumor environment require a multifaceted approach for CAR T cells to succeed for GBM. To study this, we have developed a single-chain variable fragment (scFv) specific for IL13Rα2, a GBM-associated tumor antigen, and have generated an IL13Rα2-CAR. IL13Rα2-CAR T cells only recognize IL13Rα2-positive glioma cells and had anti-glioma activity in preclinical xenograft and immune-competent animal models. However, tumors eventually recurred, paralleling the situation in humans. Major causes of treatment failure include (i) the inability of CAR T cells to persist within an immunosuppressive tumor environment, (ii) antigen-loss variants when a single antigen is targeted, and (iii) the inability of CAR T cells to efficiently traffic to tumor sites due to a mismatch between chemokines produced by the tumor and chemokine receptors expressed by CAR T cells. In mechanistic studies, we have demonstrated limited IL13Rα2-CAR T cell persistence and the development of antigen-loss variants. In addition, we showed in xenograft models that transgenic expression of IL15 in CAR T cells enhances their persistence and anti-glioma activity. However, these xenograft studies are limited; the goal of this R01 is to perform mechanistic studies in immune-competent animal models and evaluate genetic approaches to enhance the anti-glioma activity of IL13Rα2-CAR T cells. Thus, we now hypothesize that IL13Rα2-CAR T cells can be further genetically engineered to optimize their anti-GBM activity by enhancing their persistence, targeting multiple tumor antigens, and improving their trafficking to tumor sites. Aim 1 investigates whether IL15-expressing CAR T cells can resist the immunosuppressive tumor environment in syngeneic GBM models. Aim 2 optimizes CAR T cells to target both IL13Rα2 and EphA2, two glioma-associated antigens. Aim 3 investigates if trafficking of CAR T cells to GBMs can be improved by the transgenic expression of CCR2, a chemokine receptor that recognizes CCL2, a chemokine produced by GBMs. At the conclusion of the grant, we will have addressed three major hurdles of CAR T cell therapy for GBM. While we will use our data to justify the development of a future clinical study utilizing optimized IL13Rα2-CAR T cells for patients with GBMs; our modified approach to T cell therapy should be applicable to a broad range of solid tumors.

胶质母细胞瘤（GBM）是最常见和侵袭性的原发性脑肿瘤