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。在美国有大约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，并且每年有近11，000名患者死于他们的疾病。治愈率和10年生存率仍然很低，表明需要新的治疗方法。我们在体外和临床试验中已经证明，来自单倍相合供体的免疫球蛋白样受体（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。我们建议使用三管齐下的方法：a）在自体环境中应用NK细胞治疗，使所有患者的治疗成为可能; B）增强NK细胞的临床疗效。我们假设我们可以通过激活和扩增NK细胞以及通过调节NK细胞效应物与骨髓瘤靶点之间的相互作用来克服HLA-I类诱导的自体NK细胞对骨髓瘤细胞的抑制。在特定目标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细胞的扩增是重要的。如果不扩增，NK细胞将太少而无法根除所有骨髓瘤。NK细胞的“增压”将克服自体骨髓瘤递送的任何抑制信号。我们将用转染有膜结合IL 15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，我们将评估活化的自体NK细胞的作用是否可以通过用CS 1的人源化抗体标记骨髓瘤细胞来增强。CS 1是一种由骨髓瘤表达但不被正常组织表达的CD 2受体家族分子，因此赋予骨髓瘤特异性杀伤。该抗体将有效地“标记”骨髓瘤细胞，用于由NK细胞进行的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抑制性配体来增加活化的自体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。因此，我们将评估硼替佐米与活化的NK效应物组合时是否存在潜在的协同或累加效应。这种临床方法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，一旦我们证明了增强NK细胞治疗在高风险或复发性骨髓瘤患者中的疗效。此外，这项研究可能会导致对其他NK细胞敏感的恶性肿瘤更有效的治疗。 公共卫生相关性：多发性骨髓瘤是一种骨髓癌，目前无法治愈。在美国大约有54，000名骨髓瘤患者。这项拨款提案描述了3种新的方法，可以使用患者自身的免疫细胞来摧毁癌症。这种治疗也可用于治疗其他癌症。