Understanding and improving responses to adaptive NK cell therapy for leukemia and multiple myeloma

项目摘要 自然杀伤（NK）细胞是具有杀死恶性肿瘤和病毒感染的能力的强效效应淋巴细胞 细胞通过释放溶解颗粒而不需要抗原特异性。急性髓性白血病（AML）和 多发性骨髓瘤（MM）对NK细胞介导的杀伤高度敏感。使用供体NK细胞 治疗这些恶性肿瘤已经在超过三分之一的患者中产生了临床反应， 难治性AML患者最终获得治愈性骨髓移植。尽管取得了这些成功，NK细胞 治疗受到输注细胞寿命短和发生功能衰竭的限制， 当NK细胞暴露于肿瘤微环境时发生。NK细胞的一个子集，称为“适应性” 巨细胞病毒（CMV）感染后发生。适应性NK细胞比传统NK细胞寿命更长 细胞，具有强大的分泌细胞因子的能力，并且对肿瘤中的抑制具有抗性 微环境我们证明，移植后适应性NK细胞扩增与26%的 AML复发减少53%，MM复发减少53%。我们的实验室已经开发出一种可靠的方法， 从CMV血清阳性供体的外周血中扩增适应性NK细胞;然而，我们的初步数据 还显示通过活化受体NKG 2C的适应性NK细胞的慢性刺激， 与炎性细胞因子一起，诱导检查点抑制受体的高表达。我们寻求 表征作为AML或MM治疗给予的适应性NK细胞的体内行为。在目标1中，我们将 确定适应性NK细胞是否比传统NK细胞存活更长时间并运输到骨髓 在同种异体输注后。患者样本将从正在进行的I/II期临床试验中收集，使用 同种异体适应性NK细胞治疗复发性AML。此外，我们将测试适应性NK细胞的持久性， 在MM的鼠模型中，与常规NK细胞疗法相比， NK细胞衰竭的机制，并测试检查点受体阻断是否恢复NK细胞功能。 这些研究将由明尼苏达大学共济会癌症中心的艾米美利奴博士领导， 杰弗里米勒医生的指导美利奴博士目前是一名博士后研究员，但将成为一名讲师 在她完成奖学金培训后。米勒博士是NK细胞治疗的领导者， 将NK细胞生物学的发现转化为新的临床应用。明尼苏达大学 癌症中心提供了一个特殊的环境，培养转化癌症研究的职业生涯。到 为了实现成为一名独立研究者的长期目标，美利奴博士招募了一名顾问， 委员会的主要科学家，并制定了一项培训计划，旨在扩大她的知识基础， 发展她的技术专长，培养她的领导能力。

Project Summary Natural killer (NK) cells are potent, effector lymphocytes with the ability to kill malignant and virally infected cells by releasing lytic granules without the need for antigen specificity. Acute myeloid leukemia (AML) and multiple myeloma (MM) are highly susceptible to NK cell-mediated killing. Strategies using donor NK cells to treat these malignancies have yielded clinical responses in more than a third of patients, even allowing some refractory AML patients to eventually get a curative bone marrow transplant. Despite these successes, NK cell therapy has been limited by the short life span of infused cells and the occurrence of functional exhaustion that occurs when NK cells are exposed to the tumor microenvironment. A subset of NK cells, termed ‘adaptive’ develops in response to cytomegalovirus (CMV) infection. Adaptive NK cells live longer than conventional NK cells, have a robust capacity to secrete cytokines, and are resistant to suppression in the tumor microenvironment. We demonstrated that adaptive NK cell expansion after transplant is associated with a 26% reduction in AML relapse and a 53% reduction in MM relapse. Our lab has developed a reliable method to expand adaptive NK cells from peripheral blood of CMV seropositive donors; however, our preliminary data also shows that chronic stimulation of adaptive NK cells through the activating receptor NKG2C, in combination with inflammatory cytokines, induces high expression of checkpoint inhibitory receptors. We seek to characterize the in vivo behavior of adaptive NK cells given as therapy for AML or MM. In Aim 1, we will determine whether adaptive NK cells survive longer than conventional NK cells and traffic to the bone marrow after allogeneic infusion. Patient samples will be collected from an ongoing phase I/II clinical trial using allogeneic, adaptive NK cells to treat relapsed AML. In addition, we will test adaptive NK cell persistence and longevity compared to conventional NK cell therapy in a murine model of MM. In Aim 2, we will identify mechanisms of NK cell exhaustion and test whether checkpoint receptor blockade restores NK cell function. These studies will be led by Dr. Aimee Merino, at the University of Minnesota Masonic Cancer Center, under the mentorship of Dr. Jeffrey Miller. Dr. Merino is currently a postdoctoral fellow, but will become an instructor upon completion of her fellowship training. Dr. Miller is a leader in NK cellular therapy with a track record of translating discoveries in NK cell biology into novel clinical applications. The University of Minnesota Masonic Cancer Center offers an exceptional environment for cultivating a career in translational cancer research. To achieve the long-term goal of becoming an independent investigator, Dr. Merino has recruited an advisory committee of leading scientists and developed a training plan aimed at broadening her knowledge base, developing her technical expertise, and cultivating her leadership skills.