Feasibility of gamma/delta T cell immunotherapy for glioblastoma

描述（由申请人提供）：由于没有有效的治疗方法，几乎所有被诊断为高级别脑肿瘤（如多形性胶质母细胞瘤（GBM））的个体都会死于疾病。这些拟议的研究将开始探索一种新的免疫治疗策略如何使用过继转移？d - T细胞可能用于GBM的治疗。经典的a - T细胞介导的免疫反应需要抗原处理和抗原呈递细胞的mhc限制性展示（适应性免疫反应），而a - T细胞介导的免疫反应需要抗原处理和mhc限制性展示。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（先天免疫反应）。人类恶性GBM表达许多已知的靶抗原？d T细胞和扩增/活化？T细胞会溶解原代GBM和已建立的GBM细胞系。尽管在体内细胞毒性作用？在体内，抗GBM的T细胞似乎对原发肿瘤几乎没有作用——可能是由于缺乏接近肿瘤的途径，肿瘤衍生的免疫抑制，或其他因素导致功能或数量上的缺陷。T细胞室。因此，我们假设克服物理障碍和肿瘤衍生的免疫抑制将允许？d T细胞对GBM产生有效的先天反应。这一假设的检验有两个具体目的。在第一个具体目标下进行的研究将确定在何种程度上？来自GBM患者的d T细胞会扩增并杀死已建立的GBM细胞系和来自患者自身GBM的培养细胞。这一特定目的将检验自体？d T细胞治疗GBM。在特定目标2下进行的研究将确定是否在体外扩展/激活？来自健康志愿者的d - T细胞将杀死来自同一患者的已建立的GBM细胞系和原代GBM培养物。这一特定目的将检验同种异体的可行性。d T细胞治疗GBM。虽然在这一目标中没有提出治疗干预措施，但我们预计这项工作将产生重要的新的临床前数据，这将是设计我们的第一代临床试验所必需的，旨在研究如何在体外扩展？d T细胞可作为GBM的免疫疗法。多形性胶质母细胞瘤是脑肿瘤中最常见的恶性肿瘤，目前尚无有效的治疗方法。GBM很容易被免疫系统中一种叫做？d T细胞，但这些细胞似乎对正在生长的肿瘤几乎没有影响。这可能是因为？T细胞无法到达肿瘤或者因为肿瘤本身可能阻止？防止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？T细胞可以用于治疗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。

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.