TCR Gene Modified T Cells for Adoptive Immunotherapy

用于过继免疫治疗的 TCR 基因修饰 T 细胞

• 批准号: 8175611
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 203.26万
• 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/8175611
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Affinity; Antigens; Autologous; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Culture Techniques; Cell Death; Cells; Chronic; Clinical; Clinical Trials; Cloning; Conduct Clinical Trials; Engineering; Environment; Environmental Risk Factor; Frequencies; Gene Transfer; Gene-Modified; Genes; Goals; Histocompatibility Antigens Class I; Human; Immune; Immunosuppression; Infusion procedures; Laboratories; Lead; Lesion; Location; Lymphocyte Harvest; Lymphopenia; MHC Class I Genes; Malignant Neoplasms; Modeling; Mus; National Cancer Institute; Operative Surgical Procedures; Patients; Peptides; Physiological; Publishing; Reagent; Reporting; Retroviral Vector; Safety; Series; Source; Staging; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Therapeutic; Treatment Efficacy; Tumor-Infiltrating Lymphocytes; Vaccination; Viral Vector; Virus Diseases; base; cell type; cellular engineering; cellular transduction; chemotherapy; improved; improved functioning; in vivo; inhibitor/antagonist; melanoma; mouse model; neoplastic cell; novel; novel strategies; preconditioning; programs; receptor expression; response; subcutaneous; tumor

Recent clinical trials conducted at the Surgery Branch of the National Cancer Institute (NCI) has have found that adoptive transfer of autologous tumor reactive T cells into patients preconditioned with nonmyeloablative chemotherapy leads to significant durable objective clinical responses. T cells used in these studies were TIL harvested from melanoma lesions. There are two key problems that have limited its use outside the NCI. First, many patients don't have suitable tumors TIL harvest. Second, it is difficult to isolate and expand tumor reactive T cells to therapeutic numbers for most patients. New approaches for adoptive T cell transfer are needed if this approach will make it beyond the experimental stage. We published the first report demonstrating that it was feasible to redirect the reactivity of normal PBL-derived T cells using retroviral vectors encoding TCR genes isolated from a MART-1 reactive T cell clone. This opened the possibility of providing any patient with a source of autologous tumor-reactive T cells capable of recognizing any antigen so long as a TCR was available which could recognize that antigen. This MART-1 reactive TCR was the first used to treat patients with TCR gene modified T cells demonstrating the feasibility and safety of using TCR gene modified T cells in humans. However, this trial and three others had fewer objective clinical response compared to TIL suggesting TCR gene modified T cells are less effective that TIL. Based on these trials, it is clear there are critical differences between these two cells types. Over the years, the field of TCR gene transfer has focused on TCR affinity, TCR pairing, and TCR expression. The biology of T cells engineered with viral vectors has largely been unexplored. We therefore hypothesize that TCR gene modified T cells are fundamentally different than "normal" T cells in how they respond to environmental factors. We further hypothesize that a better understanding of how TCR transduced T cells are impacted by lymphopenia, T cell help, activation-induced cell death (AICD), costimulation, and immune suppression will lead to better TCR transduced T cells for patient treatment. Based on these hypotheses, we developed this Program to improve the function of TCR gene modified T cells through a series of laboratory comparing TCR transduced T cells to normal T cells bearing the same TCR. When complimented with clinical trials, our highly integrated Program will advance the field of TCR gene transfer leading to their improved therapeutic efficacy not only for patients with melanoma but for patients with other malignancies and chronic viral infections.

最近在国家癌症研究所（NCI）外科分支进行的临床试验已经发现，自体肿瘤反应性T细胞过继转移到用非清髓性化疗预处理的患者中导致显著持久的客观临床应答。这些研究中使用的T细胞是从黑素瘤病变收获的TIL。有两个关键问题限制了它在NCI之外的使用。首先，许多患者没有合适的肿瘤TIL收获。其次，对于大多数患者来说，难以分离和扩增肿瘤反应性T细胞至治疗数量。如果过继性T细胞转移的新方法将使其超越实验阶段，则需要这种方法。 我们发表了第一份报告，证明使用编码从MART-1反应性T细胞克隆分离的TCR基因的逆转录病毒载体重定向正常PBL衍生的T细胞的反应性是可行的。这为任何患者提供了能够识别任何抗原的自体肿瘤反应性T细胞来源的可能性，只要TCR可以识别该抗原。这种MART-1反应性TCR首次用于用TCR基因修饰的T细胞治疗患者，证明了在人中使用TCR基因修饰的T细胞的可行性和安全性。然而，该试验和其他三项试验与TIL相比具有较少的客观临床应答，表明TCR基因修饰的T细胞不如TIL有效。基于这些试验，很明显这两种细胞类型之间存在关键差异。 多年来，TCR基因转移领域一直专注于TCR亲和力、TCR配对和TCR表达。用病毒载体工程化的T细胞的生物学在很大程度上尚未探索。因此，我们假设TCR基因修饰的T细胞在如何响应环境因素方面与“正常”T细胞有根本不同。我们进一步假设，更好地理解TCR转导的T细胞如何受到淋巴细胞减少症、T细胞辅助、活化诱导的细胞死亡（AICD）、共刺激和免疫抑制的影响，将导致更好的TCR转导的T细胞用于患者治疗。基于这些假设，我们开发了这个程序，通过一系列的实验室比较TCR转导的T细胞与携带相同TCR的正常T细胞来改善TCR基因修饰的T细胞的功能。当与临床试验相结合时，我们高度整合的项目将推动TCR基因转移领域的发展，从而提高其不仅对黑色素瘤患者，而且对其他恶性肿瘤和慢性病毒感染患者的治疗效果。