Tailored antigen specificity for personalized adoptive T cell therapy of cancer

描述（由申请人提供）：开发用于基于细胞的癌症治疗的常规基因治疗策略在其抗原特异性方面是一致固定的，这意味着只有足够幸运的患者在其癌细胞表面上表达规定的抗原才有可能经历有意义的益处。细胞治疗领域仍然受到无法成功开发技术的阻碍，该技术提供了一个灵活的平台，用于产生具有强大效应子功能和增强的存活特性的高度个性化的抗原特异性T细胞，可广泛应用于治疗大多数晚期疾病患者。开发用于产生非MHC限制性抗原特异性T细胞的通用且灵活的平台的能力对于癌症和慢性病毒感染的过继免疫治疗具有明确且显著的临床意义。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，该系统首次通过重定向T细胞和优化T细胞存活和体内功能实现了靶向抗原特异性的灵活性。BBIR系统利用抗生物素蛋白（或抗生物素抗体）和生物素之间的极其紧密和特异性的亲和力来开发柔性CIR平台，该平台由生物素结合CIR（称为BBIR）和来源于人scFv文库的生物素化的人scFv（生物抗体）组成。通过BBIR平台，根据肿瘤表达的已知抗原阵列，通过简单地将特异性抗原生物抗体“加载”到自体T细胞上，为每个患者量身定制肿瘤反应性T细胞。在本文中，开发、表征和优化了这种新型平台，以用于体外测定系统和癌症临床前模型中的有效性。这种灵活的平台旨在为过继免疫治疗产生从头非MHC限制性肿瘤抗原特异性T细胞，推进了现有的基因治疗技术，并有利于改善疾病控制。

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.