A streamlined, high-throughput platform for validation of cancer antigen presentation and isolation of cancer antigen reactive T cells

一个简化的高通量平台，用于验证癌症抗原呈递和分离癌症抗原反应性 T 细胞

• 批准号: 10272349
• 负责人: Amy Brock
• 金额: $ 39.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10272349
• 关键词: Activities of Daily Living; Address; Adoptive Cell Transfers; Antibodies; Antigen Presentation; Antigen Targeting; Antigens; Autoimmune Diseases; Autologous; Bar Codes; Binding; Biological Models; CRISPR/Cas technology; Cancer cell line; Cell Line; Cell Lineage; Cell surface; Cells; Clinical; Clone Cells; DNA; DNA Library; Development; Engineering; Gene Expression; Generations; Genomics; Human; Immune System Diseases; In Vitro; Infection; Libraries; Link; Major Histocompatibility Complex; Malignant Neoplasms; Membrane Proteins; Methods; Organoids; Patients; Peptides; Peripheral Blood Mononuclear Cell; Population; Primary Neoplasm; Process; Reporter; Reporting; Research; Specificity; Surface; System; T cell therapy; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tumor Antigens; Tumor-Infiltrating Lymphocytes; Validation; antigen-specific T cells; base; cancer cell; cancer immunotherapy; cancer type; clinical practice; cytotoxicity; in vivo; neoantigens; neoplastic cell; patient derived xenograft model; prevent; protein biomarkers; rapid technique; screening; sensor; success; technology development; tumor

Abstract T cell receptor (TCR) based cancer immunotherapies, either infusing expanded patient autologous tumor- specific T cells or infusing cancer-specific TCR engineered autologous T cells, have shown great clinical benefit in several types of cancer. However, two challenges have prevented the broad application of these therapies to many types of cancer. First, there lacks a quick and sensitive method to detect patient-specific presentation of cancer antigen peptides on the surface of tumor cells. Second, there lacks a rapid method for the isolation of antigen-specific T cells that can be propagated quickly in vitro to meet the real-time needs of adoptive cell transfer therapy. These challenges have become road blocks for the application of TCR based cancer immunotherapy to many types of cancer and have prevented the exploration of other classes of cancer-antigens in addition to neo-antigens (NeoAs) that also have therapeutic potential, such as cancer germline antigens (CGA). In this study, we propose the development of AbTR (Antigen sensing-based T cell Recall) technology to address these two critical challenges in large scale. The AbTR technology will provide a quick and streamlined path to identify cancer antigens presented on tumor cell from hundreds of possible targets and isolate many antigen- specific T cell clones that are functionally capable of killing tumor cells and are ready to be used in adoptive cell transfer therapy. The success of the project address two urgent needs in cancer immunotherapy. This technology not only can be applied to all types of cancer but may also be relevant for the study of other immunological diseases, such as infection and autoimmune diseases.

抽象的 基于 T 细胞受体 (TCR) 的癌症免疫疗法，要么注入扩大的患者自体肿瘤 特异性 T 细胞或输注癌症特异性 TCR 工程自体 T 细胞，已显示出巨大的临床益处 在几种类型的癌症中。然而，两个挑战阻碍了这些疗法的广泛应用 许多类型的癌症。首先，缺乏一种快速、灵敏的方法来检测患者的具体表现 肿瘤细胞表面的癌抗原肽。其次，缺乏快速分离的方法。 可在体外快速增殖的抗原特异性T细胞，满足过继细胞移植的实时需求 治疗。这些挑战已成为基于TCR的癌症免疫疗法应用的障碍 多种类型的癌症，并阻止了除 也具有治疗潜力的新抗原 (NeoAs)，例如癌症种系抗原 (CGA)。 在本研究中，我们建议开发 AbTR（基于抗原传感的 T 细胞召回）技术来解决 这两个大规模的关键挑战。 AbTR 技术将提供一条快速、简化的途径 从数百个可能的目标中识别肿瘤细胞上呈递的癌症抗原，并分离出许多抗原 具有杀死肿瘤细胞功能并可用于过继细胞的特定 T 细胞克隆 转移疗法。该项目的成功解决了癌症免疫治疗的两个迫切需求。这项技术 不仅可以应用于所有类型的癌症，还可能与其他免疫学的研究相关 疾病，例如感染和自身免疫性疾病。