Off-the-Shelf Engineered Cord Blood NK Cells for the Treatment of Hematologic Malignancies.

摘要/摘要 尽管40多年前就有报道称NK细胞具有强大的杀伤功能，但过继疗法 利用这种特性对抗晚期癌细胞的策略在临床上取得的成功有限。一位少校 翻译的障碍一直是缺乏可靠的方法来增强不充分的持久性和 NK细胞输注后活性降低。因此，项目3的长期目标是设计 晚期B淋巴系恶性肿瘤(如急性淋巴母细胞癌)的新型过继细胞疗法 白血病、慢性淋巴细胞白血病和非霍奇金淋巴瘤)。中心假设是：(I)杀戮 脐带血(CB)来源的NK细胞抗血液病的功能可以显著增强 最小的不良毒性，包括移植物对宿主疾病，通过基因修饰细胞表达CD19- 特异性嵌合抗原受体(CAR)、自杀基因(诱导型caspase-9或IC9)和IL-15细胞因子 以支持NK细胞的增殖和持久性；以及(Ii)通过抑制 从而取消了NK细胞中一个关键的细胞因子信号检查点，使其有可能 考虑使用低剂量的细胞治疗，而不会失去疗效。这一组合战略基于我们的 最近的初步发现以及CAR.CD19重定向T细胞的转化成功将是 追求三个具体目标。在Aim 1，一项首个人类I/II期临床试验中，我们将评估安全性和 IC9/CAR.19/IL15转导的CB-NK细胞在36例晚期白血病患者中的抗肿瘤活性 淋巴瘤。目标2试图追踪上述转导细胞的体内命运，并将 目标1中记录的疾病反应的结果。这种方法将使我们能够解决以下几个问题 根本性问题一直是更有效的过继NK细胞治疗模式的障碍 癌症患者。最后，Aim 3将瞄准NK细胞中的细胞因子信号检查点CIS，以进一步 提高我们战略的治疗潜力。如果我们成功地避免了毒性(细胞因子释放 例如，综合症)可能与这种类型的靶向治疗相关，我们的项目将标记一个 癌症新细胞治疗方法的开发取得明显进展。

ABSTRACT / SUMMARY Despite reports of the strong killing function of NK cells more than four decades ago, adoptive therapy strategies to exploit this property against late-stage cancer cells have had limited success in the clinic. A major obstacle to translation has been the lack of reliable methods to enhance the inadequate persistence and reduced activity of NK cells after their infusion into patients. Thus, the long-term goal of Project 3 is to devise novel adoptive cell-based therapies for advanced B-lymphoid malignancies (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma). The central hypothesis is: (i) the killing function of cord blood (CB)-derived NK cells against hematologic cancers can be substantially enhanced with minimal adverse toxicity, including graft-vs.-host disease, by genetically modifying the cells to express a CD19- specific chimeric antigen receptor (CAR), a suicide gene (inducible caspase-9, or iC9) and the IL-15 cytokine to support NK cell proliferation and durability; and ( ii ) it may be feasible to boost this activity by inhibiting the CISH gene, thus abolishing a pivotal cytokine signaling checkpoint in NK cells and making it possible to consider the use of lower doses of cell therapy without loss of efficacy. This combined strategy, based on our recent preliminary findings as well as the transformative successes with CAR.CD19-redirected T cells, will be pursued in three specific aims. In Aim 1, a first-in-human phase I/II clinical trial, we will evaluate the safety and antitumor activity iC9/CAR.19/IL15-transduced CB-NK cells in 36 patients with advanced leukemia or lymphoma. Aim 2 seeks to track the in vivo fate of the transduced cells described above and correlate the findings with disease responses recorded in Aim 1. This approach will enable us to address several fundamental issues that have been persistent barriers to more effective modes of adoptive NK cell therapy for patients with cancer. Finally, Aim 3 will target CIS, a cytokine signaling checkpoint in NK cells, to further improve the therapeutic potential of our strategy. If we succeed in avoiding toxicity (cytokine release syndrome, for example) that may be associated with targeted therapies of this type, our project will mark a clear advance in the development of novel cellular treatments for cancer.