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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个GCRC应用程序将重点回答NK细胞生物学中的几个重要问题。这项研究要检验的主要假设是抑制性NK细胞受体在癌症治疗和移植中发挥作用。现在众所周知，NK细胞表达识别I类MHC分子的抑制性受体。这些受体与其MHC配体的结合提供了一种抑制信号，保护靶标不被裂解。因此，同种异体NK细胞的治疗将比自体NK细胞提供更有效的抗肿瘤治疗。这将在临床试验中进行测试(分组研究1)。子研究1将检验这一假设，即NK细胞的动态平衡扩张需要清除淋巴间隙，这将是疗效所必需的。子研究1将在急性髓细胞白血病和肾癌两个患者群体中分层进行。对于预后较差的AML患者，将使用具有抗急性白血病活性的住院化疗的高强度准备方案。这种程度的强化在临床上并不适用于肾癌。因此，将测试一种改进的、强度较低的门诊化疗方案。此外，在NK细胞发育过程中，异基因移植后重建的NK细胞的获得尚不清楚。次级研究2将重点回答这个问题，假设移植后早期重建的NK细胞受体将表现出受体的缺乏，这将具有生理相关性并与临床结果相关。了解移植中的这一过程可能有助于指导供体移植或选择供体，以提高癌症的最佳治疗效果。分研究1：“MT2003-01：急性髓系白血病和肾癌复发患者的同种异体自然杀伤细胞”。这是一项针对晚期AML患者的临床试验，这些患者在标准诱导化疗后未能获得缓解或患有转移性肾癌。这项试验是在GCRC(#679号议定书)中进行的I期临床试验的直接外推，该试验接近完成其研究目标。从I期细胞剂量递增研究中，我们得出结论：半相合的同种异体NK细胞输注是安全的，低剂量环磷酰胺和高剂量甲基强的松龙的制备方案无法抑制受体混合淋巴细胞的反应，供体细胞可以在受体外周血中找到约5天，但不会长期存在，也不会在体内扩张。这项研究的主要假设之一是，为了使同种异体NK细胞有效，它们必须在IL-2注射的两周内在体内扩张。在I期研究中未能实现这一目标可能是由于1)制备方案抑制不足和2)淋巴间隙清除不足，现在已知淋巴间隙在体内过继转移的淋巴细胞的体内平衡扩张中起重要作用。这项临床试验将解决这两个假设。选择AML作为本研究的目标人群是基于最近的骨髓移植研究，该研究表明，半相合移植预防AML复发的能力与不匹配的NK细胞受体及其推测的MHC-I类配体有关。这项研究的患者将接受一种制备方案，该方案使用两种活性白血病药物：环磷酰胺和氟达滨，具有更强的免疫抑制作用。选择包括肾细胞癌是基于新的数据显示同种异体移植后的活性，以及这种肿瘤历史上具有免疫反应性的事实。在GMP条件下，GCRC细胞治疗核心将选择并激活半相合的NK细胞。作为了解同种异体半相合NK细胞作用的一部分，将在几个时间点对供者NK细胞和患者血液进行实验室研究，以了解它们的持久性、扩增和免疫反应。

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.