Cell Therapy Core

细胞治疗核心

• 批准号: 8555364
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 104.13万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555364
• 关键词: Accounting; Adoptive Immunotherapy; Affinity; Antigens; Autologous; Biological Models; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell Therapy; Clinical; Clinical Trials; Cytolysis; Disseminated Malignant Neoplasm; Engineering; Frequencies; Gene-Modified; Genes; Goals; Human; In Vitro; Laboratories; Laboratory Study; 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; neoplastic cell; programs; response; tumor

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 of the 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 alpha and beta 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 patient 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.

最近的研究表明，对转移性癌症患者的产物T细胞转移（ACT）可能是一种有效的治疗方法。 ACT的抗原反应性T细胞的最常见来源是体内扩展的肿瘤浸润淋巴细胞（TIL）或抗原刺激的PBL衍生的T细胞。治疗ACT患者的主要局限性之一是大量抗原反应性自体T细胞的可用性。为了避免这种限制，我们首先证明，可以使用编码从肿瘤反应性T细胞克隆的TCRα和β基因的逆转录病毒载体重定向T细胞的特异性。随后，我们和其他人表明，可以分离识别多种肿瘤和病毒抗原的TCR。所得的TCR转导的T细胞可以像抗原特异性T细胞一样有效地分泌细胞因子并裂解靶标。通过鉴定第一个高亲和力人类TCR的鉴定，该领域得到了进一步的发展，该高亲和力人类TCR可以设计CD4+和CD8+ T细胞以识别肿瘤细胞表达的抗原的生理水平。这些研究和其他研究开放了向大量患者提供ACT的可能性，无论其自然能够产生抗肿瘤免疫力。 在2006年，人类据报道了TCR转导的T细胞的首次使用。这项研究的结论是，TCR基因修饰的T细胞可以安全地给予患者，并且有证据表明它们在体内的抗肿瘤活性。随后，已经发表了其他三项研究，这些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，在较高的频率下观察到客观的临床反应。然而，用TCR转导的T细胞治疗的患者（12-30％）的临床反应频率大大低于用TIL治疗的患者（〜50％）。因此，TCR转导的T细胞的生物学与TIL之间可能存在根本差异，这解释了临床反应率的差异。 该程序需要的是小鼠和人类直到13831的一致且可重复的来源 TCR转导T细胞在整个程序中使用。因此，核心C的目的是为1-4提供高质量的TIL TIL 13831 TCR转导的小鼠和人T细胞用于其体外和体内研究，并在项目5中为临床试验生成临床级TIL TIL TIL TIL TIL 13831 TCR转导的T细胞。