CMV infection and NK-cell therapy for multiple myeloma

CMV 感染和 NK 细胞治疗多发性骨髓瘤

• 批准号: 9178822
• 负责人: Katy Rezvani
• 金额: $ 21.13万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-13 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178822
• 关键词: Acute Myelocytic Leukemia; Adoptive Transfer; Adult; Affect; Allogenic; American; Americas; Antigen-Presenting Cells; Area; Autologous; Blast Cell; Blood; Blood specimen; Bone Marrow; Cell Line; Cell Therapy; Cells; Clinical; Color; Complication; Containment; Cytolysis; Cytomegalovirus; Cytomegalovirus Infections; Disease; Disease remission; Flow Cytometry; Frequencies; Growth; HLA Antigens; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; High Dose Chemotherapy; Human; Immunotherapeutic agent; Immunotherapy; In complete remission; Individual; Infusion procedures; Interleukin-15; Interleukin-2; Laboratories; Ligands; Mediating; Multiple Myeloma; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Outcome; Patients; Phenotype; Plasma Cells; Play; Procedures; Protocols documentation; Role; Signal Transduction; Specificity; Stem cell transplant; Stem cells; Surface; Techniques; Transplantation; Treatment outcome; Tumor Cell Line; Umbilical Cord Blood; Work; abstracting; base; cytotoxic; cytotoxicity; improved; innovation; killings; partial response; peripheral blood; receptor; receptor function; reconstitution; relapse risk; response; standard care; treatment response; tumor

Abstract: Multiple myeloma (MM) is the second most prevalent blood cancer affecting approximately 83,367 Americans. In 2014, it is estimated that there will be 24,050 new cases of MM and 11,090 people will die of this disease. High dose chemotherapy in combination with autologous hematopoietic stem cell transplantation (HSCT) is the standard treatment for MM; however, innovative strategies are required to improve treatment outcome as most patients fail to achieve complete remission post-transplant and 55.1% of patients die within 5 years. Cytomegalovirus (CMV) infection is a potentially fatal complication in patients receiving HSCT, but recent evidence suggests that, when properly treated, it can exert beneficial clinical outcomes. CMV reactivation is associated with a markedly reduced risk of relapse in acute myeloid leukemia (AML) patients treated with allogeneic HSCT and while the mechanism is unknown, CMV-mediated alterations in the composition of NK-cell subsets are likely involved. NK-cells also play a critical role in slowing the progression of MM and adoptive transfer of NK-cells has been used as a means of curtailing the growth of MM in humans. One possible mechanism underpinning the beneficial effect of CMV on clinical outcome in AML patients, which might be beneficial in MM patients as well, is the increased frequency of NKG2Cpos/NKG2Aneg NK-cells with CMV. NKG2C is an activating receptor and NKG2A an inhibitory receptor for the non-classical HLA class I molecule HLA-E. Thus, only NKG2Cpos/NKG2Aneg NK-cells are able to effectively kill HLA-Epos target cells. Interestingly, both AML and MM cells highly express HLA-E, which protects them from them patient NK-cells that are mostly NKG2Apos. As a result of the limited ability of patient NK-cells to target their own MM cells, immunotherapeutic procedures that rely on donor NK-cells have been developed. The infusion of allogeneic NK-cells has shown promise as a means of inducing remission in MM patients; however, efficacy is limited by the difficulty of acquiring adequate numbers of alloreactive NK-cells and high expression of NKG2A relative to NKG2C in expanded NK-cells. Thus, new protocols are needed to enhance the anti-MM activity of NK-cells. Our group has shown that latent CMV infection enhances NK-cell activity against HLA-E expressing tumor cell lines (including the MM cell line U266) through an NKG2C-dependent mechanism. In this study, we propose to extend these findings and examine the role of CMV infection and frequency of NKG2Cpos/NKG2Aneg NK-cells on early post-transplant responses in MM patients receiving autologous HSCT. We also intend to show that NKG2Cpos/NKG2Aneg NK-cells with high anti-MM activity can be preferentially expanded from fresh PBMCs and cryopreserved cord blood samples using HLA-E-transfected feeder cells. If successful, our innovative approach could improve NK-cell-based immunotherapy for the treatment of MM.

摘要：多发性骨髓瘤（MM）是影响大约83,367的第二大流行癌症 美国人。 2014年，据估计，将有24,050例新案例和11,090人死亡 疾病。高剂量化疗与自体造血干细胞移植结合 （HSCT）是MM的标准处理；但是，需要创新策略来改善治疗 结果由于大多数患者无法在移植后完成完全缓解，而55.1％的患者死亡55.1％ 年。巨细胞病毒（CMV）感染是接受HSCT的患者的潜在致命并发症，但 最近的证据表明，如果经过适当的治疗，它可以发挥有益的临床结果。 CMV 重新激活与急性髓样白血病（AML）患者复发的风险显着降低有关 用同种异体HSCT处理，虽然该机制尚不清楚，但CMV介导的改变了 NK细胞子集的组成可能涉及。 NK细胞在减慢进展方面也起着关键作用 MM和NK细胞的收养转移已被用作减少人类中MM的生长的一种手段。 CMV对AML患者的临床结果的有益作用的一种可能的机制 也可能对MM患者有益，是NKG2CPOS/NKG2ANEG NK细胞的频率增加 CMV。 NKG2C是一种激活受体，NKG2A是非经典HLA I类的抑制受体 分子HLA-E。因此，只有NKG2CPOS/NKG2ANEG NK细胞能够有效杀死HLA-EPOS靶细胞。 有趣的是，AML和MM细胞都高度表达HLA-E，可保护它们免受患者的侵害NK细胞 主要是nkg2apos。由于患者NK细胞靶向自己的MM细胞的能力有限， 已经开发了依靠供体NK细胞的免疫治疗程序。同种异体的输注 NK细胞已显示出有望作为诱导MM患者缓解的一种手段。但是，功效受到限制 获得足够数量的同种异体NK细胞和NKG2A的高表达的困难 NKG2C在扩展的NK细胞中。因此，需要新的方案来增强NK细胞的抗MM活性。 我们的小组表明，潜在CMV感染增强了针对HLA-E表达肿瘤细胞的NK细胞活性 通过NKG2C依赖性机制（包括MM细胞系U266）线（包括MM细胞系U266）。在这项研究中，我们建议 扩展这些发现并检查NKG2CPOS/NKG2ANEG NK细胞的CMV感染和频率的作用 在接受自体HSCT的MM患者中移植后的早期反应。我们还打算表明 具有较高抗MM活性的NKG2CPOS/NKG2ANEG NK细胞可以优先扩展到新鲜的PBMC和 使用HLA-E转染的馈线细胞使用冷冻保存的脐带血样品。如果成功，我们的创新 方法可以改善基于NK细胞的免疫疗法以治疗MM。