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

摘要 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 在几种癌症中。然而，有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，缺乏一种快速而灵敏的方法来检测患者特定的症状 肿瘤细胞表面的肿瘤抗原肽。第二，缺乏一种快速分离的方法 可在体外快速繁殖以满足过继细胞转移实时需求的抗原特异性T细胞 心理治疗。这些挑战已经成为基于TCR的癌症免疫疗法应用的障碍 与许多类型的癌症有关，并阻止了对其他类型癌症抗原的探索 也具有治疗潜力的新抗原(NeoA)，如癌症胚系抗原(CGA)。 在这项研究中，我们提出了基于抗原感知的T细胞召回技术的发展，以解决 这两个关键挑战都是大规模的。Abtr技术将提供一条快速而流畅的途径 从数百个可能的靶点中鉴定出现在肿瘤细胞上的癌症抗原，并分离出许多抗原- 功能上能够杀死肿瘤细胞并准备用于过继细胞的特异性T细胞克隆 转移疗法。该项目的成功解决了癌症免疫治疗中的两个迫切需求。这项技术 不仅可以应用于所有类型的癌症，而且可能与其他免疫学研究相关 疾病，如感染和自身免疫性疾病。

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.