A Universal Approach to Personalized Adoptive T cell Therapy of Cancer

描述（由申请人提供）：基因工程改造的T淋巴细胞已经成为能够在体内识别和根除实体癌和血液癌的“现成”连环杀手。表达嵌合抗原受体（汽车）的T细胞具有将基于MHC不受限制的抗体的抗原特异性与TCR-ζ和共刺激信号传导结构域偶联的能力，用于抗原触发的T细胞增殖、植入和抗肿瘤活性。尽管如此，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地在其癌细胞表面上表达规定抗原的患者才有可能经历有意义的益处，并且在具有异质性肿瘤相关抗原表达的肿瘤中可能具有有限的功效。细胞治疗领域仍然受到无法成功开发技术以提供灵活平台的阻碍， 产生高度个性化的抗原特异性T细胞，其具有稳健的效应子功能和增强的存活特性，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。我们建立在强有力的概念验证结果的基础上，以测试中心假设，即通过创新平台的再开发，CAR样疗法可以得到显着改善，并广泛应用于同时或顺序靶向多种不同抗原。这扩展了NIH在NIH R21探索/发展生物工程研究资助机制下的投资，其中可行性研究得分为1%，并以其创新性和体外和临床应用的强大潜力而闻名。现在已经成功地建立了通用免疫受体的可行性，并确定了平台改进的机会，我们现在已经准备好扩展这些有前途的研究。在这里，我们联合先进抗体开发和基于T细胞的基因工程的科学专业知识，提出1）优化通用免疫受体的构建，以增加抗体中间体结合; 2）开发TAA的治疗前基于抗体的成像，以将联合收割机与重定向T细胞治疗相结合，作为反应潜力的预测器;和3）通过免疫受体再发育和改善的肿瘤转移率来提高体内抗肿瘤功效。如本文所提出的通用免疫受体平台的成功应用被分阶段进行，以通过开发适应性系统来彻底改变CAR样基因治疗，该适应性系统允许通过重定向的T细胞和优化的T细胞存活和体内功能首次灵活地靶向抗原特异性。

DESCRIPTION (provided by applicant): Genetically engineered T lymphocytes have emerged as "off-the-shelf" serial killers capable of recognizing and eradicating solid and hematological cancers in vivo. T cells expressing chimeric antigen receptors (CARs) have the capacity of coupling MHC-unrestricted antibody-based antigen specificity with TCR-z and costimulatory signaling domains for antigen triggered T cell proliferation, engraftment and anti-tumor activity. Still, conventional gene therapy strategies developed for used in cell-based therapy for cancer are uniformly fixed in their antigen specificity, meaning only patients fortunat enough to have the prescribed antigen expressed on the surface of their cancer cells have the potential to experience meaningful benefit and may have limited efficacy in tumors with heterogeneous tumor-associated antigen expression. 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. We build upon strong proof-of-concept results to test the central hypothesis that CAR-like therapy can be dramatically improved and widely applied to target multiple and diverse antigens either simultaneously or sequentially through innovative platform re-development. This extends upon NIH investment under the NIH R21 Exploratory/Developmental Bioengineering Research Grant mechanism, where the feasibility study scored in the 1% percentile and was noted for its innovative nature and strong potential for in vitro and clinical applications. Having now successfully established feasibility for universal immune receptors and identified opportunities for platform improvement, we are now well-positioned to extend these promising studies. Here, we unite scientific expertise in advanced antibody development and T cell-based gene engineering to propose 1) to optimize universal immune receptor construction for increased antibody intermediate binding; 2) to develop pre-therapeutic antibody-based imaging of TAA to combine with redirected T cell therapy as a predictor of potential for response; and 3) to improve anti-tumor efficacy in vivo through immune receptor re-development and improved tumor penetrance. Successful application of universal immune receptor platform as proposed here is staged to revolutionize CAR-like gene therapy through development of adaptable systems that allow for the first time flexibility in targeted antigen-specificity by redirected T cells and optiized T cell survival and function in vivo.