Tailored antigen specificity for personalized adoptive T cell therapy of cancer

定制抗原特异性，用于癌症的个性化过继 T 细胞疗法

• 批准号: 8048356
• 负责人: Daniel J. Powell
• 金额: $ 17.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-06 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048356
• 关键词: Adoptive Immunotherapy; Advanced Malignant Neoplasm; Affinity; Antibodies; Antibody Specificity; Antigen Targeting; Antigens; Autologous; Avidin; Binding; Biological Assay; Biomedical Engineering; Biotin; Cancer Control; Cell Survival; Cell Therapy; Cell physiology; Chronic; Clinical; Development; Docking; Dose; Drug Kinetics; Effectiveness; Elements; Engineering; Engraftment; Funding; Generations; Genetic Engineering; Health; Health Benefit; Human; Immunologic Receptors; Immunosuppression; Immunotherapy; In Vitro; Infusion procedures; Intention; Libraries; Ligands; Longevity; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Patients; Positioning Attribute; Pre-Clinical Model; Preclinical Testing; Property; Public Health; Research; Research Project Grants; Signal Transduction; Specificity; Surface; System; T-Cell Immunologic Specificity; T-Cell Proliferation; T-Lymphocyte; Techniques; Technology; Testing; Time; Transgenes; Tumor Antigens; United States National Institutes of Health; Virus Diseases; advanced disease; antigen binding; arm; base; biotin-binding protein; cancer cell; cancer immunotherapy; cancer type; cell killing; cellular engineering; design; disorder control; experience; extracellular; flexibility; gene therapy; immuno-gene therapy; immunogenicity; improved; in vitro Assay; in vitro testing; in vivo; innovation; killings; mesothelin; neoplastic cell; novel; novel strategies; theories; tool; tumor; tumor specificity

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. 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）：用于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上均匀地固定在其抗原特异性上，这意味着只有足够幸运的患者能够在其癌细胞表面表达的处方抗原具有有意义的好处。细胞疗法领域仍然无法成功开发该技术，以提供具有鲁棒效应子功能和增强生存能力的高度个性化抗原特异性T细胞的灵活平台，并可以广泛应用大多数患有晚期疾病的患者。开发通用和灵活平台以生成非MHC限制抗原特异性T细胞的能力对癌症和慢性病毒感染的过养免疫疗法具有明显而显着的临床意义。在这项研究中，我们提出了一个生物素结合受体（BBIR）系统，该系统允许通过重定向的T细胞在靶向抗原特异性中首次柔韧性，并优化了T细胞的存活和体内功能。 BBIR系统利用了抗生物素（或抗生物素抗体）和生物素之间极为紧密和特异性的亲和力，该柔性CIR平台由生物素结合CIR（称为BBIR）和从人类SCFV库中得出的生物素结合CIR（称为BBIR）和生物素化的人类SCFV（BBIR）。使用BBIR平台，根据其肿瘤表达的一系列已知抗原阵列，只需将特定的抗原生物塑料加载到自体T细胞上，为每个患者量身定制肿瘤T细胞。本文中，这个新颖的平台是在体外测定系统和临床前模型中开发，特征和优化的。这个灵活的平台旨在生成从头非MHC限制的肿瘤抗原特异性T细胞用于过养免疫疗法，其进步存在基因治疗技术，并且拟合良好以改善疾病的控制。 公共卫生相关性：需要扩大患者对基于T细胞的治疗的创新个性化方法，以改善对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，以通过开发基于T细胞的肿瘤靶向和杀伤的通用系统来克服当前对工程T细胞疗法的局限性。这项研究的公共卫生益处将是开发高度个性化的“量身定制” T细胞平台，旨在扩大患者对癌症的有效癌症治疗的可及性。