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，或者输注扩增的患者自体肿瘤- 特异性T细胞或输注癌症特异性TCR工程化自体T细胞，已经显示出巨大的临床益处 在几种癌症中。然而，两个挑战阻碍了这些疗法的广泛应用， 多种癌症。首先，缺乏一种快速和敏感的方法来检测患者特异性的 肿瘤细胞表面的癌抗原肽。第二，缺乏快速的分离方法， 抗原特异性T细胞，可在体外快速增殖，以满足过继细胞转移的实时需求 疗法这些挑战已经成为基于TCR的癌症免疫治疗应用的障碍 许多类型的癌症，并阻止了探索其他类别的癌症抗原，除了 也具有治疗潜力的新抗原（NeoA），如癌生殖系抗原（CGA）。 在这项研究中，我们提出了AbTR（抗原传感为基础的T细胞召回）技术的发展，以解决 这两个关键的挑战。AbTR技术将提供一个快速和简化的路径， 从数百种可能靶点中鉴定肿瘤细胞上呈递的癌抗原，并分离出许多抗原- 特异性T细胞克隆，其在功能上能够杀死肿瘤细胞，并准备用于过继细胞 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，而且还可能与其他免疫学研究有关。 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.