Feasibility of gamma/delta T cell immunotherapy for glioblastoma

描述(申请人提供)：几乎所有被诊断患有高级别脑肿瘤的人，如多形性胶质母细胞瘤(GBM)，都会死于他们的疾病，因为没有有效的治疗方法。这些拟议的研究将开始探索如何利用过继转移的D T细胞治疗GBM的新的免疫治疗策略。与经久不衰的经典αT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))不同，？d T细胞可以广泛识别并立即对各种MHC样应激诱导的自身抗原(先天免疫反应)做出反应。人恶性GBM表达多种已知的dT细胞靶抗原，扩增/激活的dT细胞将溶解原代GBM和已建立的GBM细胞系。尽管？D T细胞在体内对GBM有细胞毒作用，但在体内似乎对原发肿瘤几乎没有作用--可能是由于缺乏接触肿瘤的途径，肿瘤衍生的免疫抑制，或其他导致？D T细胞隔室功能或数字缺陷的因素。因此，我们假设，克服物理障碍和肿瘤来源的免疫抑制将允许D T细胞对GBM产生有效的先天反应。对这一假设的检验有两个具体目标。在第一个特定目标下进行的研究将确定来自GBM患者的D T细胞将在多大程度上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。这一特定的目的将检验自体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体外扩增/激活的D T细胞是否会杀伤已建立的GBM细胞系和在特定目标1下积累的相同患者的原代GBM培养物。该特定目标将检验同种异体D T细胞治疗GBM的可行性。虽然在这一目标上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，这些数据将对我们第一代临床试验的设计至关重要，这些临床试验旨在研究如何将体外扩增的？D T细胞用作GBM的免疫治疗。多形性胶质母细胞瘤是最常见的脑部恶性肿瘤，目前尚无有效的治疗方法。GBM很容易被免疫系统中一种被称为dT细胞的成分杀死，但这些细胞似乎对不断生长的肿瘤几乎没有影响。这可能是因为D T细胞不能到达肿瘤，或者因为肿瘤本身可能阻止D 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而不损害正常细胞。如果成功，我们将开发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.