Invariant NKT Cells For Phase 1 Cancer Trials

描述(申请人提供)：人类和小鼠都有高度保守的T细胞群，可以识别非多态的MHC I类CD1d 蛋白。这些T细胞的不同之处在于它们表达几种细胞 表面蛋白主要存在于自然杀伤(NK)细胞和一种 保守的不变TCRα链。这些不变的NK T细胞似乎有 一种免疫调节功能，基于它们产生大量的 IL-4和干扰素-γ在体内激活后数小时内。不变量的丢失 NK T细胞与人类自身免疫性疾病的发生有关 和老鼠，但其他研究表明在抗病毒和抗肿瘤方面发挥关键作用 反应，并表明这些细胞介导的抗肿瘤作用 IL-2。人类的数据进一步表明，不变的NK T细胞减少 在晚期癌症患者中，我们已经显示出显著的下降 Inf-Gamma生产。这些发现有力地表明，经济扩张和 激活人不变NK T细胞产生干扰素-γ可产生 增强IL-2和肿瘤疫苗的抗肿瘤效应。至 测试这一假设，我们想要进行一期临床试验 体外扩增的自体不变NK T细胞。我们已经证明了人类 不变的NK T‘细胞可以很容易地在体外扩增，它们的干扰素-γ 使用IL-12可以恢复生产。这项提案的主要目标是 目的是建立不变NK T细胞体外扩增的最佳方法 用于临床试验的癌症患者细胞(AIM I)。我们还将 利用正在进行的IL-12临床试验来确定IL-12 体内治疗可增强不变的NK T细胞功能(目标2)。这些 临床前研究将被用来设计一期临床试验 肿瘤中不变的NK T细胞。具体目标是：1)建立最优 人不变NK T细胞体外扩增和激活方法的研究 细胞；2)确定体内IL-12处理是否促进体外扩增 或由不变的NK T细胞产生干扰素。

DESCRIPTION(provided by applicant): Humans and mice have a highly conserved population of T cells that recognizes the nonpolymorphic MHC class I-like CD1d protein. These T cells are distinguished by their expression of several cell surface proteins otherwise found largely on natural killer (NK) cells and by a conserved invariant TCR alpha chain. These invariant NK T cells appear to have an immunoregulatory function based upon their ability to produce large amounts of IL-4and IFN-gamma within hours of activation in vivo. The loss of invariant NK T cells has been linked to the development of autoimmune disease in humans and mice, but other studies show critical roles in anti-viral and anti-tumor responses, and indicate that these cells mediate the anti-tumor effects of IL-2. Data in humans further indicate that invariant NK T cells are decreased in patients with advanced cancer and we have shown marked decreases in their INF-gamma production. These findings strongly suggest that expansion and activation of human invariant NK T cells to produce INF-gamma could yield anti-tumor responses and enhance the effects of IL-2 and tumor vaccines. To test this hypothesis we would like to conduct a phase 1 clinical trial of in vitro expanded autologous invariant NK T cells. We have shown that human invariant NK T' cells can be readily expanded in vitro and that their INF-gamma production can be restored with IL-12. The primary objective of this proposal is to establish optimal methods for the in vitro expansion of invariant NK T cells from cancer patients for use in clinical trials (Aim I). We will also take advantage of ongoing IL-12 clinical trials to determine whether IL-12 treatment in vivo augments invariant NK T cell function (Aim 2). These pre-clinical studies will then be used to design of a phase I clinical trial of invariant NK T cells in cancer. The specific aims are to: 1) Establish optimal methods for the in vitro expansion and activation of human Invariant NK T cells; 2) Determine whether IL-12 treatment in vivo enhances in vitro expansion or INF production by invariant NK T cells.