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: 7678631
• 负责人: Frits van Rhee
• 金额: $ 30.09万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-22 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678631
• 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，大约有54,000名骨髓瘤患者，2007年将被诊断出20,000名新患者，每年将有近11,000名患者屈服于患病。治愈率和10年生存率仍然很低，表明需要新疗法。我们已经表明，抗性性骨髓瘤可以通过杀手型细胞免疫球蛋白喜欢的受体（KIR）配体（-l）从单位相同的体外供体和临床试验中的NK细胞不匹配的NK细胞杀死。但是，我们只有30％的患者可以找到一个KIR-L不匹配的供体。我们建议使用一种三管齐下的方法来：a）在自体设置中应用NK细胞疗法，使所有患者成为可能的治疗，b）提高NK细胞的临床疗效。我们假设我们可以通过激活和扩展NK细胞并调节NK细胞效应子与骨髓瘤靶标之间的相互作用来克服HLA级I对骨髓瘤细胞诱导的自体NK细胞的抑制。在特定目标1中，我们将通过扩展和激活骨髓瘤患者的NK细胞来确定NK细胞剂量和效力是否可以可靠地提高。如果要克服骨髓瘤负担，NK细胞的扩展很重要。没有扩展，NK细胞将消除所有骨髓瘤。 NK细胞的“增压”将克服自体骨髓瘤传递的任何抑制信号。我们将用膜结合的IL15转染的K562细胞刺激NK细胞，而共刺激分子4-1BB-L。在特定的目标2中，我们将通过标记具有人源化抗体的CS1的骨髓瘤细胞来评估活化自体NK细胞的作用。 CS1是由骨髓瘤表达但不是正常组织表达的CD2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“ FLAG”骨髓瘤细胞，用于NK细胞ADCC介导的杀伤。在特定的目标3中，我们将通过蛋白酶体抑制作用调节抑制性配体对骨髓瘤的抑制性配体来确定活化自体NK细胞的作用是否可以增加。由于HLA I类在骨髓瘤细胞上与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，我们可以在用蛋白酶体抑制剂硼替佐米治疗后在体外和体内降低HLA级I，这转化为自体NK细胞杀死骨髓瘤。因此，我们将评估将硼替佐米与活化的NK效应子相结合时的潜在协同或加性效应的存在。一旦我们证明了增强的NK细胞疗法在高风险或复发性骨髓瘤的患者中，这种临床方法可以应用于具有更好的生长控制和更耐用的缓解患者。此外，这项研究可能会导致对其他NK细胞敏感恶性肿瘤的更有效治疗。 公共卫生相关性：多发性骨髓瘤是目前无法治愈的骨髓癌的一种形式。美国大约有54,000名骨髓瘤患者。该赠款提案描述了3种新方法，可以使用患者自身的免疫细胞来破坏癌症。这种治疗也可能对治疗其他癌症有用。