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，过继性T细胞转移（ACT）可以成为转移性癌症患者的有效治疗方法。ACT最常见的抗原反应性T细胞来源是体外扩增的肿瘤浸润淋巴细胞（TIL）或抗原刺激的pbl衍生T细胞。治疗ACT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。为了规避这一限制，我们首先证明了使用从肿瘤反应性T细胞克隆中分离的编码TCR α和β基因的逆转录病毒载体来重定向T细胞特异性是可能的。随后，我们和其他人已经证明，有可能分离出识别多种肿瘤和病毒抗原的TCR。由此产生的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和裂解靶标。该领域的进一步发展是鉴定出第一个高亲和力的人TCR，它可以使CD4+和CD8+ T细胞识别肿瘤细胞表达的生理水平的抗原。这些研究和其他研究开启了向大量患者提供ACT的可能性，无论他们的自然能力如何产生抗肿瘤免疫。