CELL THERAPY CORE

细胞治疗核心

• 批准号: 8744942
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 101.08万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-04 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744942
• 关键词: Accounting; Adoptive Immunotherapy; Affinity; Antigens; Autologous; Biological Models; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell Culture Techniques; Clinical; Clinical Trials; Cytolysis; Disseminated Malignant Neoplasm; Engineering; Ensure; Frequencies; Gene-Modified; Genes; Goals; Human; In Vitro; Infusion procedures; Instruction; Knockout Mice; Laboratories; Laboratory Study; Mouse Strains; Mus; Parents; Patients; Physiological; Publishing; Reporting; Retroviral Vector; Safety; Source; T-Cell Immunologic Specificity; T-Lymphocyte; Transgenic Mice; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Viral Tumor Antigens; cytokine; effective therapy; in vivo; meetings; mouse model; named group; neoplastic cell; novel; programs; research study; response; tumor; vector

PROJECT SUMMARY (See instructions): Recent studies have shown that adoptive T cell transfer (ACT) can be an effective treatment for patients with metastatic cancer. The most common source of antigen reactive T cells for ACT is ex vivo expanded tumor infiltrating lymphocytes (TIL) or antigen stimulated PBL-derived T cells. One ofthe main limitations to treating patients with ACT is the availability of large numbers of antigen reactive autologous T cells. To circumvent this limitation, we first demonstrated that it was possible to redirect the specificity of T cells using retroviral vectors encoding the TCR a and p genes isolated from a tumor-reactive T cell clone. Subsequently, we and others have shown that it is possible to isolate TCR's that recognize a wide variety of tumor and viral antigens. The resulting TCR transduced T cells can secrete cytokines and lyse targets as efficiently as antigen specific T cells. The field was further advanced by the identification of the first high affinity human TCR that could engineer both CD4+ and CD8+ T cells to recognize the physiologic levels of antigen expressed by tumor cells. These studies and others have open the possibility of providing ACT to a large number of patients regardless of their natural ability to generate anti-tumor immunity. In 2006, the first use of TCR transduced T cells was reported in humans. The conclusions from this study were that TCR gene modified T cells can be safely administered to patients and there was evidence of their anti-tumor activity in vivo. Subsequently, three other studies have been published which support the safety of using TCR transduced T cells in cancer patients. In these studies, objective clinical responses were observed at higher frequencies when high affinity TCRs were used. However, the frequency of the clinical responses in patients treated with TCR transduced T cells (12-30%) was substantially less than in patients treated with TIL (~50%). Therefore, there may be fundamental differences between the biology of TCR transduced T cells and TIL which account for the differences in the clinical response rates. What is needed for this Program is a consistent and reproducible source of mouse and human TIL 13831 TCR transduced T cells for use throughout the Program. Therefore, the goal of Core C is to provide Projects 1-4 with high quality TIL 13831 TCR transduced mouse and human T cells for their in vitro and in vivo studies and to generate clinical grade TIL 13831 TCR transduced T cells for the clinical trials in Project 5.

项目总结（见说明）： 最近的研究表明，过继性T细胞转移（ACT）可以是转移性癌症患者的有效治疗方法。用于ACT的抗原反应性T细胞的最常见来源是离体扩增的肿瘤浸润淋巴细胞（TIL）或抗原刺激的PBL衍生的T细胞。用ACT治疗患者的主要限制之一是大量抗原反应性自体T细胞的可用性。为了规避这种限制，我们首先证明了使用编码从肿瘤反应性T细胞克隆分离的TCR α和β基因的逆转录病毒载体来重定向T细胞的特异性是可能的。随后，我们和其他人已经表明，有可能分离出识别各种肿瘤和病毒抗原的TCR。所得TCR转导的T细胞可以分泌细胞因子并与抗原特异性T细胞一样有效地裂解靶标。通过鉴定第一个高亲和力人TCR进一步推进了该领域，该TCR可以工程化CD 4+和CD 8 + T细胞以识别由肿瘤细胞表达的生理水平的抗原。这些研究和其他研究开辟了向大量患者提供ACT的可能性，无论他们产生抗肿瘤免疫的天然能力如何。在2006年，报道了TCR转导的T细胞在人类中的首次使用。这项研究的结论是，TCR基因修饰的T细胞可以安全地施用于患者，并且有证据表明它们在体内具有抗肿瘤活性。随后，发表了另外三项研究，支持在癌症患者中使用TCR转导的T细胞的安全性。在这些研究中，当使用高亲和力TCR时，以较高频率观察到客观临床应答。然而，用TCR转导的T细胞治疗的患者中的临床应答频率（12-30%）显著低于用TIL治疗的患者（~50%）。因此，TCR转导的T细胞和TIL的生物学之间可能存在根本差异，这是临床应答率差异的原因。该计划所需要的是用于整个计划的小鼠和人TIL 13831 TCR转导的T细胞的一致且可再现的来源。因此，核心C的目标是为项目1-4提供高质量的TIL 13831 TCR转导的小鼠和人T细胞用于其体外和体内研究，并为项目5中的临床试验产生临床级TIL 13831 TCR转导的T细胞。