Tailored antigen specificity for personalized adoptive T cell therapy of cancer

描述(由申请人提供)：为癌症细胞治疗开发的传统基因治疗策略一致地固定在其抗原特异性上，这意味着只有足够幸运地在其癌细胞表面表达处方抗原的患者才有可能体验到有意义的益处。由于无法成功地开发技术来提供一个灵活的平台来生成高度个性化的抗原特异性T细胞，该T细胞具有强大的效应功能和增强的生存特性，可以广泛应用于大多数晚期疾病的治疗，这一点仍然阻碍着细胞治疗领域的发展。开发一个通用和灵活的平台来产生非MHC限制性抗原特异性T细胞的能力对癌症和慢性病毒感染的过继免疫治疗具有明确和重要的临床意义。在这项研究中，我们提出了一种生物素结合免疫受体(BBIR)系统，该系统首次允许通过重定向T细胞来灵活地靶向抗原特异性，并优化T细胞在体内的存活和功能。BBIR系统利用亲和素(或抗生物素抗体)与生物素之间极其紧密和特异的亲和力，开发了一种灵活的CIR平台，该平台由生物素结合的CIR(简称BBIR)和来自人scFv文库的生物素化的人单链抗体(生物体)组成。利用BBIR平台，肿瘤反应性T细胞是为每个患者量身定做的，只需根据他们的肿瘤表达的已知抗原阵列将特定的抗原生物体加载到自体T细胞上即可。在这里，这一新的平台被开发、表征和优化，用于体外检测系统和癌症临床前模型的有效性。这个灵活的平台旨在产生用于过继免疫治疗的从头开始的非MHC限制性肿瘤抗原特异性T细胞，促进了现有的基因治疗技术，并处于改善疾病控制的有利地位。

DESCRIPTION (provided by applicant): Conventional gene therapy strategies developed for used in cell-based therapy for cancer are uniformly fixed in their antigen specificity, meaning only patients fortunate enough to have the prescribed antigen expressed on the surface of their cancer cells have the potential to experience meaningful benefit. The cellular therapy field remains hindered by the inability to successfully develop the technology to deliver a flexible platform for the generation of highly personalized antigen-specific T cells with robust effector function and enhanced survival properties that can be widely applied for the treatment of the majority of patients with advanced disease. The capacity to develop a universal and flexible platform for the generation of non-MHC-restricted antigen-specific T cells has clear and significant clinical implications for adoptive immunotherapy of cancer and chronic viral infection. In this study, we propose a Biotin Binding Immune Receptor (BBIR) system that allows for the first time flexibility in targeted antigen-specificity by redirected T cells and optimized T cell survival and function in vivo. The BBIR system capitalizes on the extremely tight and specific affinity between avidin (or anti-biotin antibody) and biotin in the development of a flexible CIR platform comprised of a biotin- binding CIR (referred to as BBIR) and biotinylated human scFvs (biobodies) derived from a human scFv library. With the BBIR platform, tumor-reactive T cells are tailor-made for each patient by simply "loading" specific antigen biobodies onto autologous T cells according to the array of known antigens expressed by their tumor. Herein, this novel platform is developed, characterized and optimized for effectiveness in in vitro assay systems and in preclinical models of cancer. This flexible platform, designed to generate de novo non-MHC-restricted tumor antigen-specific T cells for adoptive immunotherapy, advances existent gene therapy technology and is well-positioned to improve the control of disease.