Project 5 - Memory-like NK cell augmented hematopoietic cell transplantation for AML.

项目摘要/摘要 该项目的长期目标是将免疫学领域的新发现转化为早期阶段。 白血病患者的免疫治疗临床试验。异基因造血细胞移植(HCT)是 对于高危或复发的AML是一种标准的治疗方法，具有潜在的治愈作用。然而，主要障碍是 老年AML患者的成功包括1)无法耐受强化调理，2)疾病复发，3) 移植物抗宿主病(GVHD)，以及4)在许多情况下缺乏合适的供者。一个关键的免疫玩家 在调节移植物抗白血病(GVL)效应的过程中，也可能限制GVHD的是NK细胞。我们 假设NK细胞生物学的新发现可以转化为临床，以提高疗效和 老年AML患者对红细胞压积的耐受性。 最近的临床研究报告了来自MHC单倍体相合的供者的HCT 合并HCT后环磷酰胺的清髓性预适应方案的临床结果 与匹配的无血缘关系捐赠者的红细胞压积相当。然而，治疗AML的一个主要障碍是 单纯性红细胞压积的患者是大量的老年患者，他们只是降低强度的候选者 条件反射(RIC)，导致与治疗相关的死亡率较低，但代价是发病率高得多 到目前为止，急性髓细胞白血病复发的长期无病存活率很低。为了解决这一领域的重要障碍， 我们将在即刻用相同供者记忆样的NK细胞过继免疫治疗来加强HCT HCT后阶段，在潜在改善植入和最小化GVHD的同时，提高GVL。 最近有报道指出，NK细胞在联合细胞因子作用下表现出“记忆样”特性 预激活。我们和其他人已经证实，人类记忆样的NK细胞在 二次刺激，并具有多种抗肿瘤特性。我们已经将其转化为一种细胞疗法 复发/难治(REL/REF)AML患者，并已完成1期研究。然而，这样做的一个缺点是 异基因NK细胞疗法是受者在2-3周后恢复免疫系统的排斥反应， 为这些NK细胞消除急性髓系白血病提供了一个短暂的“机会之窗”。要解决此限制，请在 在NK免疫治疗领域，我们将纳入供者匹配的RIC HCT，提供理想的免疫相容 记忆样NK细胞扩增和攻击残留AML的环境。 在这项提案中，我们将1)测试使用相同供体记忆增强RIC Hct的安全性和有效性- 就像急性髓细胞白血病患者第二阶段临床试验中的NK细胞过继免疫治疗一样，2)定义记忆样NK 细胞与临床反应的相关性，并阐明记忆样NK细胞抗AML的关键机制 回应。这些研究将导致对NK细胞有效攻击机制的新理解 AML，并由此AML抵抗NK细胞治疗，因此提高记忆样NK细胞抗 急性髓系白血病在未来临床试验中的反应。

Project Summary/Abstract The long-term goals of this project are to translate novel findings in the field of immunology into early phase immunotherapy clinical trials for patients with leukemia. Allogeneic hematopoietic cell transplantation (HCT) is a standard treatment for high-risk or relapsed AML and is potentially curative. However, major barriers to success in older AML patients include 1) an inability to tolerate intensive conditioning, 2) disease relapse, 3) graft-versus-host disease (GVHD), and 4) the lack of a suitable donor in many cases. One key immune player in mediating the graft-versus-leukemia (GvL) effect that also potentially limits GVHD is the NK cell. We hypothesize that new findings in NK cell biology can be translated to the clinic to improve the effectiveness and tolerability of HCT in older AML patients. Recent clinical studies have reported that HCT from an MHC-haploidentical donor (haplo-HCT) with myeloablative conditioning regimens that incorporate post-HCT cyclophosphamide results in clinical outcomes that are comparable to HCT from matched unrelated donors. However, one major obstacle to treating AML patients with haplo-HCT is the large number of older patients that are only candidates for reduced-intensity conditioning (RIC), which results in lower treatment-related mortality, but at the cost of a much higher incidence of AML relapse, and thus far, poor long-term disease-free survival. To address this important hurdle in the field, we will augment HCT with same-donor memory-like NK cell adoptive immunotherapy during the immediate post-HCT period, to enhance GvL while potentially improving engraftment and minimizing GVHD. Reports have recently identified that NK cells exhibit “memory-like” properties following combined cytokine pre-activation. We and others have established that human memory-like NK cells respond robustly after a second stimulation and have multiple anti-tumor properties. We have translated this into a cellular therapy for relapsed/refractory (rel/ref) AML patients, and have completed a phase 1 study. However, one drawback of this allogeneic NK cell therapy is its rejection by the recipient's recovering immune system after 2-3 weeks, providing a short “window of opportunity” for these NK cells to eliminate AML. To address this limitation in the NK immunotherapy field, we will incorporate a donor-matched RIC HCT, providing an ideal immune-compatible environment for memory-like NK cells to expand and attack residual AML. In this proposal, we will 1) test the safety and efficacy of augmenting RIC HCT with same-donor memory- like NK cell adoptive immunotherapy in a phase 2 clinical trial for patients with AML, 2) define memory-like NK cell correlates of clinical response, and elucidate key mechanisms important for memory-like NK cell anti-AML responses. These studies will lead to a new understanding of mechanisms whereby NK cells effectively attack AML, and whereby AML resists NK cell therapy, and hence strategies to improve memory-like NK cell anti- AML responses in future clinical trials.