Feasibility of gamma/delta T cell immunotherapy for glioblastoma

描述（由申请人提供）：几乎所有被诊断患有高级别脑肿瘤（如多形性胶质母细胞瘤（GBM））的个体都将死于其疾病，因为没有有效的治疗方法。这些拟议的研究将开始探讨如何一种新的免疫策略，使用过继转移？d T细胞可用于GBM的治疗。不像经典的a-T细胞介导的免疫反应，需要抗原加工和抗原呈递细胞的MHC限制性展示（适应性免疫反应），？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（先天免疫应答）。人类恶性GBM表达许多已知的靶抗原？d T细胞，并扩增/活化？d T细胞将裂解原代GBM和建立的GBM细胞系。尽管在体内的细胞毒性作用？d T细胞对GBM，似乎对原发性肿瘤在体内的影响不大-可能是由于缺乏进入肿瘤，肿瘤衍生的免疫抑制，或其他因素，导致功能或数字赤字？d T细胞区室。因此，我们假设，克服物理障碍和肿瘤源性免疫抑制将允许？d T细胞以产生对GBM的有效先天性应答。这一假设的测试是在两个具体的目标。在第一个具体目标下进行的研究将确定在多大程度上？来自GBM患者的d T细胞将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。本文将具体探讨自体移植的可行性。d用于GBM的T细胞疗法。根据特定目标2进行的研究将确定是否离体扩增/活化？d来自健康志愿者的T细胞将杀死已建立的GBM细胞系和来自特定目标1中累积的相同患者的原代GBM培养物。这一具体目标将研究的可行性同种异体？d用于GBM的T细胞疗法。虽然没有治疗干预措施提出了这一目标，我们预计，这项工作将产生重要的新的临床前数据，这将是必不可少的设计，我们的第一代临床试验，旨在研究如何离体扩大？d T细胞可用作GBM的免疫疗法。多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，目前尚无有效的治疗方法。GBM很容易被免疫系统的一种成分杀死，这种成分被称为？d T细胞，但这些细胞似乎对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T细胞的增殖。我们将测试有希望的方法，可能克服这些问题，以确定是否？d T细胞可用于治疗GBM而不损害正常细胞。如果成功的话，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.