Potentiating Natural Killer Cell Anti-Myeloma Effects

增强自然杀伤细胞的抗骨髓瘤作用

• 批准号: 7913482
• 负责人: JOSHUA EPSTEIN
• 金额: $ 36.82万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913482
• 关键词: Activated Natural Killer Cell; Affect; Aftercare; Allogenic; Antibodies; Applications Grants; Autologous; Binding; Bone Marrow; Bortezomib; Cell Line; Cell Therapy; Cell surface; Cell-Mediated Cytolysis; Cells; Clinical; Clinical Trials; Cytolysis; Data; Detection; Diagnosis; Disadvantaged; Disease; Disease remission; Dose; Down-Regulation; Family; Growth; Health; Hematopoietic; High Dose Chemotherapy; Immune; Immunoglobulins; In Vitro; In complete remission; Interleukin-15; K-562; K562 Cells; Killer Cells; Lead; Ligands; Lymphoma; Malignant Neoplasms; Measures; Mediating; Membrane; Modality; Multiple Myeloma; Natural Killer Cells; Normal tissue morphology; Outcome; Patients; Peripheral Stem Cell Transplantation; Pharmaceutical Preparations; Proteasome Inhibition; Proteasome Inhibitor; Refractory; Relapse; Research; Resistance; Risk; Signal Transduction; Testing; Therapeutic; Translating; cell killing; chemotherapy; clinical efficacy; cytotoxicity; high risk; humanized antibody; improved; in vivo; killer inhibitory receptor; killings; novel; novel therapeutics; outcome forecast; pilot trial; prevent; public health relevance; receptor; rituximab

DESCRIPTION (provided by applicant): Data indicate that multiple myeloma is a major health problem. There are approximately 54,000 myeloma patients in the USA, 20,000 new patients will be diagnosed with myeloma in 2007, and nearly 11,000 patients succumb to their disease yearly. The cure rate and 10-year survival remains low indicating the need for new therapies. We have shown that chemo-resistant myeloma can be killed by killer-cell immunoglobulin- like receptor (KIR) ligand (-L) mismatched NK cells from a haplo-identical donor in vitro and in a clinical trial. However, we could find a KIR-L mismatched donor for only 30% of patients. We propose to use a 3-pronged approach to: a) apply NK cell therapy in the autologous setting making therapy possible for all patients and b) enhance the clinical efficacy of NK cells. We hypothesize that we can overcome the inhibition of autologous NK cells induced by HLA-class I on myeloma cells by activating and expanding the NK cells and by modulating the interaction between NK cell effectors and myeloma targets. In Specific Aim 1 we will determine if NK cell dose and potency can be reliably increased by expanding and activating NK cells from myeloma patients. Expansion of NK cells is important if we are to overcome the myeloma burden. Without expansion, there will be too few NK cells to eradicate all myeloma. `Supercharging' of the NK cells will overcome any inhibitory signals delivered by autologous myeloma. We will stimulate the NK cells with K562 cells transfected with membrane-bound IL15 and the co-stimulatory molecule 4-1BB-L. In Specific Aim 2 we will evaluate whether the action of activated autologous NK cells can be enhanced by flagging myeloma cells with a humanized antibody to CS1. CS1 is a CD2 receptor family molecule expressed by myeloma but not by normal tissues, therefore conferring myeloma-specific killing. This antibody will effectively `flag' myeloma cells for ADCC-mediated killing by NK cells. In Specific Aim 3 we will ascertain if the action of activated autologous NK cells can be increased by down regulating inhibitory ligands on myeloma by proteasome inhibition. NK cells do not normally kill autologous myeloma due to the interaction between HLA class I on myeloma cells with inhibitory receptors on NK cells. We have demonstrated that we can down regulate HLA-class I on myeloma in vitro and in vivo after treatment with the proteasome inhibitor bortezomib and that this translates into killing of myeloma by autologous NK cells. Hence, we will evaluate the existence of potential synergistic or additive effects when combining bortezomib with activated NK effectors. This clinical approach can be applied to patients with standard-risk myeloma to obtain even better growth control and more durable remissions once we have demonstrated the efficacy of enhanced NK cell therapy in patients with high-risk or relapsing myeloma. In addition, this research could lead to more efficacious treatment for other NK cell sensitive malignancies. PUBLIC HEALTH RELEVANCE: Multiple myeloma is a form of bone marrow cancer that is currently incurable. There are approximately 54,000 myeloma patients in the USA. This grant proposal describes 3 new ways in which the patient's own immune cells can be used to destroy the cancer. Such treatment may also be useful to treat other cancers.

描述（由申请人提供）：数据表明多发性骨髓瘤是一个主要的健康问题。美国大约有54,000名骨髓瘤患者，2007年将有20,000名新患者被诊断患有骨髓瘤，每年有近11,000名患者死于该病。治愈率和 10 年生存率仍然很低，表明需要新的疗法。我们已经在体外和临床试验中证明，来自单倍体供体的杀伤细胞免疫球蛋白样受体 (KIR) 配体 (-L) 不匹配的 NK 细胞可以杀死化疗耐药性骨髓瘤。然而，我们只能为 30% 的患者找到 KIR-L 不匹配的供体。我们建议采用三管齐下的方法：a）在自体环境中应用 NK 细胞疗法，使所有患者都能接受治疗；b）增强 NK 细胞的临床疗效。我们假设，通过激活和扩增 NK 细胞以及调节 NK 细胞效应器与骨髓瘤靶标之间的相互作用，可以克服 HLA-I 类诱导的自体 NK 细胞对骨髓瘤细胞的抑制。在具体目标 1 中，我们将确定是否可以通过扩增和激活骨髓瘤患者的 NK 细胞来可靠地增加 NK 细胞的剂量和效力。如果我们要克服骨髓瘤负担，NK 细胞的扩增非常重要。如果不进行扩增，NK 细胞就会太少而无法根除所有骨髓瘤。 NK 细胞的“增压”将克服自体骨髓瘤传递的任何抑制信号。我们将用转染膜结合 IL15 和共刺激分子 4-1BB-L 的 K562 细胞刺激 NK 细胞。在具体目标 2 中，我们将评估是否可以通过使用 CS1 人源化抗体标记骨髓瘤细胞来增强激活的自体 NK 细胞的作用。 CS1 是骨髓瘤表达的 CD2 受体家族分子，但正常组织不表达，因此具有骨髓瘤特异性杀伤作用。该抗体将有效地“标记”骨髓瘤细胞，以供 NK 细胞进行 ADCC 介导的杀伤。在具体目标 3 中，我们将确定是否可以通过蛋白酶体抑制下调骨髓瘤的抑制性配体来增强激活的自体 NK 细胞的作用。由于骨髓瘤细胞上的 HLA I 类与 NK 细胞上的抑制性受体之间的相互作用，NK 细胞通常不会杀死自体骨髓瘤。我们已经证明，在用蛋白酶体抑制剂硼替佐米治疗后，我们可以在体外和体内下调骨髓瘤上的 HLA-I 类，这转化为自体 NK 细胞对骨髓瘤的杀伤作用。因此，我们将评估硼替佐米与激活的 NK 效应物联合使用时是否存在潜在的协同或相加效应。一旦我们证明了增强 NK 细胞疗法对高风险或复发性骨髓瘤患者的疗效，这种临床方法就可以应用于标准风险骨髓瘤患者，以获得更好的生长控制和更持久的缓解。此外，这项研究可能会为其他 NK 细胞敏感恶性肿瘤提供更有效的治疗。 公共卫生相关性：多发性骨髓瘤是一种目前无法治愈的骨髓癌。美国大约有 54,000 名骨髓瘤患者。该拨款提案描述了 3 种利用患者自身免疫细胞消灭癌症的新方法。这种治疗也可用于治疗其他癌症。