MT2004-25: ALLOGENEIC NATURAL KILLER CELLS WITH RELAPSED ACUTE MYELOGENOUS LEUKE

MT2004-25：复发性急性髓性白血病的同种异体自然杀伤细胞

• 批准号: 7375901
• 负责人: Jeffrey Boone Miller
• 金额: $ 4.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375901
• 关键词: MT2004; 25; ALLOGENEIC; NATURAL; KILLER

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This GCRC application will focus on answering several important questions in NK cell biology. The main hypothesis to be tested in this study is that inhibitory NK cell receptors play a role in the therapy of cancer and transplantation. It is now well known that NK cells express inhibitory receptors that recognize class I MHC molecules. Engagement of these receptors by their MHC ligands provides an inhibitory signal which protects targets from being lysed. Therefore, it follows that therapy will allogeneic NK cells bearing receptors mismatched for class I MHC ligands may provide more effective anti-tumor therapy than autologous NK cells. This will be tested in a clinical trial (Sub-Study 1). Sub-Study 1 will test the hypothesis that clearance of lymphoid space is required for homeostatic expansion of NK cells, which will be required for efficacy. Sub-Study 1 will be stratified among two patient populations, AML and renal cell carcinoma. In poor prognosis AML patients, an intense preparative regimen using in-patient chemotherapy that has activity against acute leukemia will be used. This degree of intensity is not clinically warranted in renal cell carcinoma. Therefore, a modified, less intense regimen using out-patient chemotherapy will be tested. In addition, during NK cell development, the acquisition of NK cell reconstituting after allogeneic transplant is unknown. Sub-study 2 will focus on answering this question with the hypothesis that NK cell receptors reconstituting early after transplant will exhibit a paucity of receptors which will be of physiologic relevance and correlate wil clinical outcomes. Understanding this process in transplantation may allow maipulation of donor grafts or donor selection to enhance optimal therapy of cancer. Sub-Study 1: "MT2003-01: Allogeneic natural killer cells in patients with reapse of acute myelogenous leukemia and renal cell carcinoma". This is a clinical trial in advanced patients with AML who fail to achieve remission after standard induction chemotherapy or have metastatic renal cell carcinoma. This trial is a direct extrapolation of a phase I clinical trial performed in the GCRC (Protocol #679) which is nearing completion of its study goals. From that phase I cell dose escalation study, we conclude that haploidentical allogeneic NK cell infusions are safe, that the preparative regimen of low-dose cytoxan and high-dose methylprednisolone is unable to suppress recipient mixed lymphocyte reactivity and that donor cells can be found in recipient peripheral blood for approximately five days but that do not persist long term and do not expand in vivo. One of the main hypotheses for this study is that for allogeneic NK cells to be efficacious they must expand in vivo during the two week period of IL-2 administration. Failure to achieve this goal in the phase I study may be due to 1) inadequate suppression of the preparative regimen and 2) inadequate clearance of lymphoid space, now known to be important in homeostatic expansion of adoptively transferred lymphocytes in vivo. This clinical trial will address both of those hypotheses. The choice of AML as a target population for this study is based on recent bone marrow transplant studies showing that the ability of haploidentical transplants to protect against AML reapse is associated with mismatched NK cell receptors and their presumed MHC class I ligands. Patients on this study will receive a preparative regimen which is more immunosuppressive using two active leukemia drugs: cyclophosphomide and fludarbine. The choice of including renal cell carcinoma is based on new data showing activity after allogeneic transplant and the fact that this tumor is historically immune responsive. Haploidentical NK cells will be selected and activated in the GCRC Cell Therapy Core under GMP conditions. As a part of understanding the role of allogeneic haploidentical NK cells, laboratory studies will be performed on donor NK cells and patient blood at several time points to understand their persistence, expansion and immunologic response.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。该GCRC应用程序将着重于回答NK细胞生物学中的几个重要问题。在这项研究中要检验的主要假设是抑制性NK细胞受体在癌症和移植的治疗中起作用。现在众所周知，NK细胞表达识别I类MHC分子的抑制性受体。这些受体通过其MHC配体的参与提供了一个抑制信号，可保护靶标免受裂解。因此，因此，与自体NK细胞相比，疗法将使I类MHC配体的受体异基因NK细胞可能提供更有效的抗肿瘤疗法。这将在临床试验（子研究1）中进行测试。子研究1将检验以下假设：NK细胞的稳态扩张需要淋巴样空间的清除率，这是疗效所必需的。子研究1将在两个患者种群分别分层，即AML和肾细胞癌。在不良预后的AML患者中，将使用患有针对急性白血病的活性的强烈制备方案。在肾细胞癌中，这种强度在临床上不保证。因此，将测试一种使用门诊化疗的改良，不太强烈的方案。此外，在NK细胞发育过程中，同种异体移植后NK细胞重建的采集尚不清楚。子研究2将以以下假设来回答这个问题：移植后早期重新建立的NK细胞受体将表现出很少的受体，而受体将具有生理相关性并与WIL临床结局相关。理解移植过程中的这一过程可能会使供体移植物或选择供体的选择来增强癌症的最佳治疗。子研究1：“ MT2003-01：急性粒细胞性白血病和肾细胞癌患者的同种异体天然杀伤细胞”。这是一项针对AML晚期患者的临床试验，他们在标准诱导化疗或患有转移性肾细胞癌后无法缓解。该试验是在GCRC（协议＃679）中进行的I期临床试验的直接推断，该试验即将完成其研究目标。从该第一阶段的细胞剂量升级研究中，我们得出结论，单倍性同种NK细胞输注是安全的，低剂量的细胞质和高剂量甲基甲基苯甲酸酮的制备方案无法抑制受体混合淋巴细胞反应性，并且可以在受体中延伸五天，而是在五天内延伸，但在五天内均无法发现供体细胞。这项研究的主要假设之一是，要使同种异体NK细胞有效，它们必须在IL-2给药的两周内在体内扩展。在第一阶段研究中未能实现这一目标可能是由于1）抑制制剂方案不足和2）2）淋巴空间的清除不足，现在已知在体生中采用转移的淋巴细胞的稳态扩张中很重要。该临床试验将解决这两个假设。 AML作为本研究的目标人群的选择是基于最近的骨髓移植研究，表明单倍性移植可预防AML REAPSE的能力与不匹配的NK细胞受体及其假定的MHC I类配体有关。这项研究中的患者将接受一种制剂治疗方案，使用两种活性白血病药物：环磷磷和氟达宾。包括肾细胞癌的选择是基于新的数据，显示了同种异体移植后活性以及该肿瘤在历史上具有免疫反应性的事实。在GMP条件下，将在GCRC细胞疗法核心中选择并激活单倍体NK细胞。作为理解同种异体单位NK细胞的作用的一部分，将在几个时间点上对供体NK细胞和患者血液进行实验室研究，以了解其持久性，扩张和免疫学反应。