Feasibility of gamma/delta T cell immunotherapy for glioblastoma

γ/δ T 细胞免疫治疗胶质母细胞瘤的可行性

• 批准号: 7313172
• 负责人: LAWRENCE S LAMB
• 金额: $ 15.86万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313172
• 关键词: Address; Adjuvant; Allogenic; Antigen Targeting; Antigen-Presenting Cells; Apoptosis; Appendix; Autoantigens; Autologous; Biological; Biological Assay; Brain Neoplasms; Cell Line; Cells; Clinical; Clinical Trials; Cultured Cells; Cytolysis; Data; Development; Diagnosis; Disease; Future; Generations; Glioblastoma; Human; Immune; Immune response; Immune system; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Intracranial Neoplasms; Knowledge; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Methodology; Methods; Mitogens; Normal Cell; Nude Mice; Numbers; Patients; Pre-Clinical Model; Primary Neoplasm; Procedures; Process; Regulation; Relative (related person); Reporting; Research Personnel; Resistance; Signal Pathway; Solutions; Standards of Weights and Measures; Stress; T-Lymphocyte; Testing; Therapeutic Intervention; Therapeutic immunosuppression; Translations; Tumor Cell Line; Tumor-Derived; United States Food and Drug Administration; Work; antigen processing; base; cell mediated immune response; clinical application; cytotoxic; cytotoxicity; design; healthy volunteer; in vivo; killings; novel; novel strategies; peripheral blood; pre-clinical; prevent; response; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Almost all individuals diagnosed with high-grade brain tumors such as glioblastoma multiforme (GBM) will die of their disease as no effective therapies exist. These proposed studies will begin to explore how a novel immunotherapeutic strategy using adoptively transferred ?d T cells might be exploited for the treatment of GBM. Unlike the prolonged classical a¿ T cell-mediated immune response which requires antigen processing and MHC-restricted display by antigen-presenting cells (adaptive immune response), ?d T cells can broadly recognize and immediately respond to a variety of MHC-like stress-induced self antigens (innate immune response). Human malignant GBM express many known target antigens for ?d T cells, and expanded/activated ?d T cells will lyse primary GBM and established GBM cell lines. Despite the in vivo cytotoxic effect of ?d T cells against GBM, there appears to be little effect against primary tumor in vivo -possibly due to lack of access to tumor, tumor-derived immunosuppression, or other factors that result in functional or numeric deficits in the ?d T cell compartment. Consequently we hypothesize that overcoming physical barriers and tumor-derived immune suppression will permit ?d T cells to mount an effective innate response to GBM. The test of this hypothesis is addressed in two specific aims. Studies conducted under the first specific aim will determine the extent to which ?d T cells from GBM patients will expand and kill established GBM cell lines and cultured cells from the patient's own GBM. This specific aim will examine the feasibility of autologous ?d T cell therapy for GBM. Studies conducted under specific aim 2 will determine whether or not ex vivo expanded/activated ?d T cells from healthy volunteers will kill established GBM cell lines and primary GBM cultures from the same patients accrued in Specific Aim 1. This specific aim will examine the feasibility of allogeneic ?d T cell therapy for GBM. Although no therapeutic interventions are proposed in this aim, we anticipate that this work will generate significant new preclinical data which will be essential for the design of our first generation clinical trials intended to examine how ex vivo expanded ?d T cells can be used as immunotherapy for GBM. At present, there is no effective treatment for glioblastoma multiforme (GBM), the most common malignant brain tumor. GBM is vulnerable to killing by a component of the immune system known as ?d T cells, but these cells appear to have little effect on the growing tumor. This is possibly because the ?d T cells cannot get to the tumor or because the tumor may itself prevent the ?d T cells from attacking it. We will test promising methods that may overcome these problems to determine if ?d T cells can be used as therapy against GBM without harming normal cells. If successful, we will then develop studies to treat human patients.

描述（由申请人提供）：几乎所有被诊断患有高级别脑肿瘤（例如多形性胶质母细胞瘤（GBM））的个体都会死于这种疾病，因为不存在有效的治疗方法。这些拟议的研究将开始探索如何利用过继转移的 γd T 细胞的新型免疫治疗策略来治疗 GBM。与需要抗原呈递细胞进行抗原加工和 MHC 限制性展示（适应性免疫反应）的长时间经典 a¿T 细胞介导的免疫反应不同，?d T 细胞可以广泛识别并立即响应各种 MHC 样应激诱导的自身抗原（先天性免疫反应）。人类恶性GBM表达许多已知的γd T细胞靶抗原，并且扩增/激活的γd T细胞将裂解原代GBM和已建立的GBM细胞系。尽管γd T细胞对GBM具有体内细胞毒性作用，但对体内原发性肿瘤似乎没有什么作用——可能是由于无法接近肿瘤、肿瘤源性免​​疫抑制或导致γd T细胞区室功能或数量缺陷的其他因素。因此，我们假设克服物理障碍和肿瘤源性免​​疫抑制将允许γd T 细胞对 GBM 产生有效的先天反应。该假设的检验有两个具体目标。第一个具体目标下进行的研究将确定来自 GBM 患者的 δT 细胞扩增和杀死已建立的 GBM 细胞系和来自患者自身 GBM 的培养细胞的程度。这一具体目标将检验自体 γd T 细胞治疗 GBM 的可行性。在特定目标 2 下进行的研究将确定来自健康志愿者的离体扩增/激活的 δd T 细胞是否会杀死在特定目标 1 中获得的已建立的 GBM 细胞系和来自同一患者的原代 GBM 培养物。该特定目标将检查同种异体 δd T 细胞治疗 GBM 的可行性。尽管没有在此目的中提出治疗干预措施，但我们预计这项工作将产生重要的新临床前数据，这对于设计我们的第一代临床试验至关重要，该临床试验旨在检查离体扩增的 ?d T 细胞如何用作 GBM 的免疫疗法。目前，多形性胶质母细胞瘤（GBM）这种最常见的恶性脑肿瘤尚无有效的治疗方法。 GBM 很容易被免疫系统中称为 d T 细胞的成分杀死，但这些细胞似乎对生长中的肿瘤几乎没有影响。这可能是因为γd T 细胞无法到达肿瘤，或者因为肿瘤本身可能阻止γd T 细胞攻击它。我们将测试可能克服这些问题的有前景的方法，以确定 d T 细胞是否可以用于治疗 GBM，而不伤害正常细胞。如果成功，我们将开展治疗人类患者的研究。