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）：为用于基于细胞的癌症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的患者在其癌​​细胞表面表达了规定的抗原才有潜力体验有意义的好处。细胞治疗领域仍然受到阻碍，因为无法成功开发一种技术来提供灵活的平台来生成高度个性化的抗原特异性 T 细胞，这些 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疾病的治疗。患有晚期疾病的患者。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。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 细胞在体内的存活和功能，实现了靶向抗原特异性的灵活性。 BBIR系统利用亲和素（或抗生物素抗体）和生物素之间极其紧密和特异的亲和力，开发了由生物素结合CIR（简称BBIR）和生物素化人scFv（生物体）组成的灵活CIR平台源自人类 scFv 文库。借助 BBIR 平台，只需根据患者肿瘤表达的已知抗原阵列，将特定抗原生物体“加载”到自体 T 细胞上，即可为每位患者量身定制肿瘤反应性 T 细胞。在此，开发、表征和优化了这个新颖的平台，以提高体外测定系统和癌症临床前模型的有效性。这个灵活的平台旨在从头生成用于过继免疫治疗的非 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，并有能力改善疾病的控制。 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。