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: 7869514
• 负责人: LAWRENCE S LAMB
• 金额: $ 7.12万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869514
• 关键词: Address; Allogenic; Antigen Targeting; Antigen-Presenting Cells; Autoantigens; Autologous; Brain Neoplasms; Cell Line; Cell Therapy; Cells; Clinical Trials; Cultured Cells; Cytolysis; Data; Diagnosis; Disease; Generations; Glioblastoma; Human; Immune; Immune response; Immune system; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Individual; Malignant - descriptor; Malignant neoplasm of brain; Methods; Normal Cell; Patients; Primary Neoplasm; Stress; T-Lymphocyte; Testing; Therapeutic Intervention; Tumor-Derived; Work; antigen processing; cell mediated immune response; cytotoxic; design; effective therapy; healthy volunteer; in vivo; killings; novel; pre-clinical; prevent; response; tumor

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（由适用提供）：几乎所有被诊断出患有高级脑肿瘤的人，例如胶质母细胞瘤（GBM），因为不存在有效的疗法，因此死于其疾病。这些提出的研究将开始探索如何使用适当转移的新型免疫治疗策略来探索用于治疗GBM的细胞。与长时间的经典A介导的免疫响应不同，它需要抗原抗原呈递细胞（适应性免疫响应）抗原加工和MHC限制的表现，也可以广泛识别并立即对MHC类似MHC的压力诱导的自我抗原（Insate ImmunoreSpesse）作出反应。人类恶性GBM表达了许多已知的靶抗原，用于？D T细胞，扩展/激活？D T细胞将裂解一级GBM并确定的GBM细胞系。尽管？D T细胞对GBM具有体内细胞毒性作用，但由于缺乏获得肿瘤，肿瘤衍生的免疫抑制的访问，对原发性肿瘤的作用似乎很小，或者导致功能或数值的其他因素在？因此，我们假设克服物理屏障和肿瘤衍生的免疫抑制作用将允许d t细胞具有对GBM的有效先天反应。该假设的检验在两个具体目的中得到了解决。以第一个特定目的进行的研究将决定GBM患者的d T细胞在多大程度上将扩展并杀死已建立的GBM细胞系和患者自己的GBM培养细胞的培养细胞。这个具体目标将检查自体疗法对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是否扩展/激活？D T细胞是否会杀死已建立的GBM细胞系和来自特定目标中相同患者的原发性GBM培养物。该特定目的将检查GBM的同种异体？D T细胞治疗的可行性。尽管在此目标中没有提出过治疗性干预措施，但我们预计这项工作将产生重要的新临床前数据，这对于我们的第一代临床试验的设计至关重要，旨在研究如何将体内扩展？D T细胞可以用作GBM的免疫疗法。目前，尚无对最常见的恶性脑肿瘤（GBM）胶质母细胞瘤（GBM）的有效治疗方法。 GBM容易被称为“ D T细胞的免疫系统的组成部分杀死），但是这些细胞似乎对生长的肿瘤几乎没有影响。这是可能的，因为？D T细胞无法进入肿瘤，或者是因为肿瘤本身可能会阻止？D T细胞攻击它。我们将测试可能克服这些问题的有希望的方法，以确定是否可以将t细胞用作针对GBM的治疗而不会损害正常细胞。如果成功，我们将开展研究以治疗人类患者。