Developmental Therapeutics

发育治疗学

基本信息

批准号：
8555167
负责人：
Frits van Rhee
金额：
$ 32.62万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-05 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8555167
关键词：
Activated Natural Killer Cell Affect Allogenic Animal Model Antibodies Autologous B-Lymphocytes Binding Blood Component Removal Bortezomib CD34 gene Cell Communication Cell Therapy Cell surface Cells Cessation of life Clinical Clinical Research Clinical Trials Coculture Techniques Cytolysis Data Developmental Therapeutics Program Disease Disease remission Drug resistance Drug-sensitive Engraftment Family Foundations Funding Gene Expression Profile Gene Expression Profiling Genes Goals Growth HLA Antigens Homologous Transplantation Human Activities Immunoglobulins Immunotherapy In Vitro In complete remission Interleukin-15 K562 Cells Killer Cells Ligands Malignant Neoplasms Mediating Membrane Methods Modeling Multiple Myeloma Mus NK Cell Activation Natural Killer Cells Outcome Patients Pharmaceutical Preparations Phase Population Recruitment Activity Refractory Regimen Relapse Reporting Research Resistance SCID-hu Mice Stem cells Surface T-Lymphocyte Testing Transfusion Transplantation Tumor Burden Work Xenograft Model antibody-dependent cell cytotoxicity base chemotherapy clinical application clinical efficacy conditioning cytotoxic design early experience experience graft vs host disease high risk in vivo killings mouse model neoplastic cell novel outcome forecast patient population pilot trial preclinical study receptor rituximab scale up tumor

项目摘要

Most patients with relapsed/refractory myeloma have a high-risk gene expression profile. These patients have poor long-term outcomes with salvage strategies, including transplantation-based therapies and the application of novel drugs. We conducted a pilot trial for relapsed/refractory myeloma patients in which we infused killer cell immunoglobulin-like receptor ligand (KIR-L)-mismatched natural killer (NK) cells from haplo-identical family donors in the setting of an autologous transplant. Such cells have demonstrated remarkable antileukemic effects in the allogeneic transplant setting. Our pilot trial established that transfusions of NK cells were safe, did not cause graft-versus-host disease, and did not affect engraftment of autologous CD34+ stem cells. Additional findings lay the foundation for the work proposed in Project 2. First, we observed that inhibitory KIR-Ls on myeloma cells are down-regulated in vivo after administration of bortezomib, further sensitizing myeloma cells to alloreactive (alio-) NK cell lysis. Second, CS1-specific antibody (Ab) has significant activity against primary myeloma cells in our SCID-hu mouse model, and this activity is synergistic with bortezomib. Third, we have expanded and activated NK cells with K562 cells transfected with membrane-bound interieukin-15 (IL-15) and the costimulatory molecule 4-1 BBL, increasing the number of allo-NK cells available for killing myeloma by rendering subpopulations of previously nonalloreactive NK cells cytotoxic. Specific Aim 1 will evaluate in a clinical trial whether the combination of bortezomib and CS1 Ab can enhance the antimyeloma activity of KIR-L-mismatched NK cells by down-regulating KIR-Ls on myeloma cells and invoking Ab-dependent cellular cytotoxicity, respectively. Specific Aim 2 will examine the activity of human allo-NK cells activated/expanded with K562 cell transfectants in the NOD/SCID/IL2rgamma[null]-hu model, which is deficient of murine NK cells. The potential additive/synergistic effects of combinations of bortezomib, CS1 Ab, and activated/expanded allo-NK cells will be investigated in order to design highly effective allo-NK cell therapy. Once proven effective in the relapsed high-risk disease setting, such therapy could be incorporated into upfront therapy of myeloma patients and be a useful adjunct to autotransplantation and/or novel drugs. This research may also be valuable for developing more efficacious therapies for other NK cell-sensitive malignancies.

大多数复发/难治性骨髓瘤患者的基因表达谱。这些患者的长期结局不良，包括基于移植的疗法和新型药物的应用。我们对复发/难治性骨髓瘤患者进行了试验试验，其中我们从单倍型自体移植的环境中注入了来自单普罗体育家庭供体的杀手型细胞免疫球蛋白样受体配体（KIR-L）匹配的天然杀手（NK）细胞。这些细胞在同种异体移植设置中表现出显着的抗白血病作用。我们的试点试验确定，NK细胞的输血是安全的，没有引起移植物抗宿主病，并且不影响自体CD34+干细胞的植入。其他发现为项目2中提出的工作奠定了基础。首先，我们观察到给药后，对骨髓瘤细胞对骨髓瘤细胞的抑制作用在体内下调，进一步使骨髓瘤细胞对同种异体反应性（ALIO-）NK细胞溶解。其次，CS1特异性抗体（AB）在我们的SCID-HU小鼠模型中对原发性骨髓瘤细胞具有显着的活性，并且该活性与硼替佐米是协同作用。第三，我们已经用膜结合的Interieukin-15（IL-15）转染的K562细胞扩展和激活了NK细胞，并通过4-1 bbl进行了刺激性分子，增加了可用于通过呈现先前非吸收性NK细胞细胞细胞的亚群来杀死骨髓瘤的同种NK细胞的数量。具体目标1将在临床试验中评估硼替佐米和CS1 AB的组合是否可以通过下调KIR-LS对骨髓瘤细胞上的KIR-LS并分别引起AB依赖性细胞毒性来增强KIR-L匹配的NK细胞的抗肌瘤活性。具体的目标2将检查在NOD/SCID/IL2RGAMMA [NULL] -HU模型中被K562细胞转染剂激活/扩展的人类Allo-NK细胞的活性，该模型缺乏鼠NK细胞的缺乏。为了设计高效的Allo-NK细胞疗法，研究将研究硼替佐米，CS1 AB和活化/扩展的Allo-NK细胞的潜在添加/协同作用。一旦被证明有效地在复发的高危疾病环境中有效，就可以将这种疗法纳入骨髓瘤患者的前期治疗中，并成为自养生和/或新型药物的有用辅助手段。这项研究对于为其他NK细胞敏感性恶性肿瘤开发更有效的疗法也可能很有价值。