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: 8514547
• 负责人: Daniel J. Powell
• 金额: $ 31.21万
• 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/8514547
• 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.

描述（由申请人提供）：基因工程T淋巴细胞已经成为“现成的”连环杀手，能够识别和根除体内实体和血液系统癌症。表达嵌合抗原受体（CARs）的T细胞具有将mhc不受限制的基于抗体的抗原特异性与TCR-z和共刺激信号域偶联的能力，用于抗原触发的T细胞增殖、植入和抗肿瘤活性。尽管如此，用于肿瘤细胞治疗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可能体验到有意义的益处，并且可能对具有异质肿瘤相关抗原表达的肿瘤具有有限的疗效。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