A Universal Approach to Personalized Adoptive T cell Therapy of Cancer

癌症个性化过继 T 细胞治疗的通用方法

• 批准号: 8344455
• 负责人: Daniel J. Powell
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344455
• 关键词: Adoptive Immunotherapy; Advanced Malignant Neoplasm; Antibodies; Antibody Specificity; Antigen Receptors; Antigen Targeting; Antigens; Avidity; Binding; Biological Assay; Biomedical Engineering; Biotin; Cancer Model; Cell Survival; Cell Therapy; Cell physiology; Cellular biology; Chronic; Clinical; Combination Drug Therapy; Coupling; Development; Docking; Dose; Drug Kinetics; Engineered Gene; Engineering; Engraftment; Feasibility Studies; Generations; Genetic Engineering; Health; Health Benefit; Human; Image; Immune; Immunologic Receptors; Immunotherapy; In Vitro; Investments; Ligands; Malignant Neoplasms; Mediating; Modification; Nature; Patients; Penetrance; Positioning Attribute; Property; Public Health; Reagent; Receptor Signaling; Research; Research Project Grants; Signal Transduction; Solid; Specificity; Staging; Surface; System; T cell therapy; T-Cell Development; T-Cell Immunologic Specificity; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic antibodies; Time; Tumor Antigens; United States National Institutes of Health; Virus Diseases; advanced disease; antigen binding; aptamer; base; biotin-binding protein; cancer cell; cancer therapy; cell killing; cellular engineering; clinical application; design; experience; extracellular; flexibility; gene therapy; improved; in vitro testing; in vivo; innovation; killings; neoplastic cell; novel; prognostic; receptor; response; theories; tumor; tumor specificity

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. PUBLIC HEALTH RELEVANCE: Innovative personalized approaches that broaden patient accessibility to T cell-based therapy are required to improve the control of advanced cancer and enhance health. In this study, we propose a pioneering approach to overcome the current limitations to engineered T cell therapy through the development of a universal system of T cell-based tumor targeting and killing. The public health benefit of this research will be the development of a highly personalized, "tailor-made" T cells based platform designed to broaden patient accessibility to effective T cell-based therapy of cancer.

描述（由申请人提供）：基因工程T淋巴细胞已成为能够识别和根除体内实体癌和血液癌的“现成”连环杀手。表达嵌合抗原受体 (CAR) 的 T 细胞能够将基于 MHC 非限制性抗体的抗原特异性与 TCR-z 和共刺激信号结构域耦合，以实现抗原触发的 T 细胞增殖、植入和抗肿瘤活性。尽管如此，为用于癌症细胞治疗而开发的传统基因治疗策略在其抗原特异性上是统一固定的，这意味着只有足够幸运，在其癌细胞表面表达指定抗原的患者才有可能获得有意义的益处，并且对于具有异质肿瘤相关抗原表达的肿瘤，其疗效可能有限。由于无法成功开发技术来提供灵活的平台，细胞治疗领域仍然受到阻碍。 产生高度个性化的抗原特异性T细胞，具有强大的效应功能和增强的生存特性，可广泛应用于大多数晚期疾病患者的治疗。开发通用且灵活的平台来生成非 MHC 限制性抗原特异性 T 细胞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重要的临床意义。我们以强有力的概念验证结果为基础来测试中心假设，即通过创新平台重新开发，类 CAR 疗法可以显着改善并广泛应用于同时或顺序靶向多种不同的抗原。这延伸了 NIH 在 NIH R21 探索性/发展性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%，并因其创新性和体外和临床应用的强大潜力而闻名。现在已经成功确定了通用免疫受体的可行性并确定了平台改进的机会，我们现在已经做好了扩展这些有希望的研究的准备。在这里，我们结合了先进抗体开发和基于 T 细胞的基因工程方面的科学专业知识，提出了以下建议：1) 优化通用免疫受体构建以增加抗体中间结合； 2) 开发基于治疗前抗体的 TAA 成像，与重定向 T 细胞疗法相结合，作为潜在反应的预测因子； 3）通过免疫受体的重新开发和提高肿瘤外显率来提高体内抗肿瘤功效。本文提出的通用免疫受体平台的成功应用将通过开发适应性系统彻底改变类 CAR 基因疗法，该系统首次通过重定向 T 细胞和优化 T 细胞在体内的存活和功能实现靶向抗原特异性的灵活性。 公共卫生相关性：需要创新的个性化方法来扩大患者接受 T 细胞治疗的机会，以改善晚期癌症的控制并增强健康。在这项研究中，我们提出了一种开创性的方法，通过开发基于 T 细胞的肿瘤靶向和杀伤通用系统来克服目前工程化 T 细胞疗法的局限性。这项研究的公共健康效益将是开发一个高度个性化、“量身定制”的基于 T 细胞的平台，旨在扩大患者获得有效的基于 T 细胞的癌症疗法的机会。