Invariant NKT Cells For Phase 1 Cancer Trials

描述（由申请人提供）：人和小鼠具有高度保守的 识别非多态性MHC I类CD 1d的T细胞群 蛋白这些T细胞通过它们表达几种细胞因子而被区分。 表面蛋白，否则发现主要是自然杀伤细胞（NK细胞）和由一个 保守不变的TCR α链。这些不变的NK T细胞似乎具有 免疫调节功能基于它们产生大量 IL-4和IFN-γ在体内活化数小时内的表达。不变量的损失 NK T细胞与人类自身免疫性疾病的发展有关 但其他研究显示， 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， INF-γ生产。这些发现强烈表明，扩张和 激活人类不变的NK T细胞产生INF-γ可以产生 抗肿瘤反应，并增强IL-2和肿瘤疫苗的效果。到 为了验证这一假设，我们想进行一项1期临床试验， 体外扩增自体不变NK T细胞。我们已经证明， 不变的NK T细胞可以容易地在体外扩增，并且它们的INF-γ IL-12可以恢复生产。本提案的主要目的是 建立体外扩增恒定NK T的最佳方法 来自癌症患者的细胞用于临床试验（Aim I）。我们还将 利用正在进行的IL-12临床试验来确定IL-12是否 体内治疗增强不变的NK T细胞功能（目的2）。这些 临床前研究将用于设计I期临床试验， 癌症中的恒定NK T细胞。具体目标是：（1）建立最优的 体外扩增和活化人恒定NK T的方法 2）确定体内IL-12处理是否增强体外扩增 或由不变NK T细胞产生INF。

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.