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

摘要/总结 尽管四十多年前就有报道称NK细胞具有强大的杀伤功能， 利用这种特性对抗晚期癌细胞的策略在临床上取得了有限的成功。一个主要 翻译的障碍一直是缺乏可靠的方法来提高持续性不足， NK细胞输注到患者体内后活性降低。因此，项目3的长期目标是设计 用于晚期B淋巴恶性肿瘤（如急性淋巴母细胞性 白血病、慢性淋巴细胞白血病和非霍奇金淋巴瘤）。核心假设是：（一）杀人 脐带血（CB）来源的NK细胞对抗血液学癌症的功能可以显著增强， 最小的不良毒性，包括移植物与宿主疾病，通过遗传修饰细胞以表达CD 19- 特异性嵌合抗原受体（CAR）、自杀基因（诱导型胱天蛋白酶-9或iC 9）和IL-15细胞因子 支持NK细胞增殖和持久性;和（ii）通过抑制NK细胞的增殖和持久性来增强这种活性可能是可行的。 CISH基因，从而消除了NK细胞中的关键细胞因子信号检查点，并使其成为可能。 考虑使用较低剂量的细胞疗法而不损失功效。这一综合战略，基于我们的 最近的初步发现以及CAR.CD19重定向T细胞的变革性成功，将是 追求三个具体目标。在目标1中，第一次在人体I/II期临床试验，我们将评估安全性和 iC 9/CAR.19/IL 15转导的CB-NK细胞在36例晚期白血病患者中的抗肿瘤活性，或 淋巴瘤目的2试图追踪上述转导细胞的体内命运，并将转导细胞的体内命运与其自身的基因表达相关联。 目标1中记录的疾病反应结果。这种方法将使我们能够解决几个问题。 这些基本问题一直是更有效的过继NK细胞治疗模式的持续障碍， 癌症患者。最后，Aim 3将靶向CIS，即NK细胞中的细胞因子信号检查点，以进一步 提高我们策略的治疗潜力如果我们成功地避免了毒性（细胞因子释放 综合征，例如），可能与这种类型的靶向治疗有关，我们的项目将标志着一个 在癌症的新型细胞疗法的发展方面取得了明显的进展。

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.