多发性骨髓瘤的免疫治疗研究现状

近年来,多发性骨髓瘤的治疗策略发生了重大的演变.随着对其发病机制的认识不断深入,人们发现免疫紊乱是骨髓瘤细胞逃避免疫监视、导致疾病进展的关键因素.免疫治疗通过重塑免疫微环境,恢复免疫功能,增强抗肿瘤免疫应答,成为目前较有前景的疗法.本文结合国内外相关文献对多发性骨髓瘤的免疫治疗研究现状作一综述.     

多发性骨髓瘤免疫治疗的新瞻望

多发性骨髓瘤（ＭＭ）因其患者发病年龄较大,缓解率低,复发率高而使传统的化疗以至骨髓移植等治疗结果不甚理想,本文就ＭＭ的免疫治疗（包括细胞因子,干扰素,单克隆抗体,过继免疫治疗,肿瘤疫苗及对突状细胞等）进行综述。     

多发性骨髓瘤的免疫治疗

多发性骨髓瘤(MM)的发生、发展与机体免疫功能缺陷密切相关.传统的化疗多注重于直接杀伤MM细胞,患者接受化疗后不良反应较大,生活质量较低.更为重要的是,绝大多数MM患者接受化疗后,疾病进展或复发.免疫治疗因其导致的不良反应少,靶向性强,而有望成为治愈MM的新型治疗手段.笔者拟就有关MM免疫治疗的细胞免疫治疗、体液免疫治疗、放射免疫治疗及免疫调节剂4个方面的现状及进展进行综述.     

免疫治疗在多发性骨髓瘤中的研究进展

多发性骨髓瘤(multiple myeloma, MM)是浆细胞的恶性肿瘤,约占血液系统恶性肿瘤的10%,是一种尚不能完全治愈的恶性肿瘤。免疫治疗作为MM的一种治疗策略一直在不断的深入研究中,有效的免疫治疗可以显著改善MM患者的生存质量。近年来MM的免疫治疗策略也不断有新的进展,本文将从单克隆抗体、嵌合抗原受体(chimeric antigen receptor,CAR)及浆样树突状细胞(pDC)等方面对MM近年来的免疫治疗进展进行综述。     

多发性骨髓瘤细胞粘附分子的表达及意义

多发性骨髓瘤（ＭＭ）的恶性浆细胞表达一系列细胞粘附分子,使恶性浆细胞或浆细胞的前体细胞选择性粘附并归巢于骨髓基质,并产生一系列细胞因子,这些骨髓基质细胞及细胞因子,促进恶性浆细胞增殖,并使恶性浆细胞具有不朽性,在ＭＭ的发生及发展中起重要作用。     

骨髓微环境对多发性骨髓瘤细胞microRNA-21和microRNA-30b表达的影响

目的 研究骨髓微环境对多发性骨髓瘤(MM)细胞mieroRNA(miR)-21和miR-30b的调变作用.方法培养破骨细胞,采用MACS法分选纯化CD138*骨髓瘤细胞.采用实时定量PCR的方法检测MM患者瘤细胞和细胞株以及与破骨细胞共培养的MM患者瘤细胞miR-21和miR-30b的表达量.结果 MM患者的外周血单个核细胞经破骨细胞培养基培养后10～14 d形成破骨细胞,瘤细胞与破骨细胞共培养组和未与破骨细胞共培养组相比较,细胞活力明显增高,miR-21的表达量增高了1.3～5.9倍,miR-30b表达量降低27.5%～76.9%.在正常浆细胞、MM患者瘤细胞和MM细胞株,miR-21表达水平分别为1.9±0.8、6.5±4.9和35.1±36.2,而miR-30表达分别为13.6±1.8、7.2±6.3和4.5±1.9.结论骨髓微环境可调控miR-21和miR-30b的表达,miR-21起癌基因作用,而miR-30b起抑痛基因作用.     

多发性骨髓瘤分子水平治疗的新策略

随着传统化疗、干扰素及干细胞移植的发展,多发性骨髓瘤的治疗取得了很大进步,但仍存在耐药及易复发等问题。为了进一步改善骨髓瘤患者的预后,在分子水平治疗方面出现了一些新的策略, 如以骨髓新生血管、细胞表面受体、骨髓瘤细胞DNA分子作为靶点,促进骨髓瘤细胞的凋亡,调节骨髓微环境,或是调节骨髓微环境与骨髓瘤细胞间的相互作用。这些新的治疗方法在临床及动物试验中已取得一定疗效。     

多发性骨髓瘤龛位

既往研究提示造血干细胞(HSC)的自我更新、分化等生物学特性受骨髓内特定的微环境即龛位调节.HSC龛位由黏附分子、细胞表达的信号分子、骨髓基质细胞、血管内皮细胞和成骨细胞等非细胞与细胞成分构成.近期多项研究提示在骨髓瘤的发生、发展过程中,骨髓中也存在与HSC龛位类似的骨髓瘤细胞龛位.骨髓瘤细胞通过细胞间直接接触,或可溶...     

多发性骨髓瘤龛位

既往研究提示造血十细胞（HSC）的自我更新、分化等生物学特性受骨髓内特定的微环境即龛位调节。HSC龛位由黏附分子、细胞表达的信号分子、骨髓基质细胞、血管内皮细胞和成骨细胞等非细胞与细胞成分构成。近期多项研究提示在骨髓瘤的发生、发展过程中,骨髓中也存在与HSC龛位类似的骨髓瘤细胞龛位。骨髓瘤细胞通过细胞间直接接触,或可溶性因子的分泌诱导其周围骨髓微环境出现多种异常,产生适合骨髓瘤（于）细胞的龛位,而骨髓瘤细胞龛位反过来参与骨髓瘤（干）细胞的自我更新、分化、耐药等过程。本文就骨髓瘤细胞的龛位作一综述。     

多发性骨髓瘤免疫治疗的新瞻望

多发性骨髓瘤(MM)因其患者发病年龄较大,缓解率低,复发率高而使传统的化疗以至骨髓移植等治疗结果不甚理想。本文就MM的免疫治疗(包括细胞因子、干扰素、单克隆抗体、过继免疫治疗、肿瘤疫苗及树突状细胞等)进行综述。     

Humoral immunotherapy of multiple myeloma: perspectives and perplexities

Importance of the field: Multiple myeloma (MM) is a hematological malignancy still remaining incurable despite the various therapies available, mainly because of the high fraction of refractory/relapsing cases. Therefore, the development of novel therapeutic approaches is urgently needed to overcome conventional treatment resistance.

Areas covered in this review: In the era of targeted therapies, treatments combining a high specificity for neoplastic cells and the capability to interfere with environmental signals should be regarded as the weapons of choice. Monoclonal antibody (mAb)-based humoral immunotherapy could satisfy both these requirements when applied to MM. Indeed, many of the molecules expressed on MM cells, such as CD38, CD40, CD49d, CD138 and CD162 are involved in the adhesive dynamics regulating the crosstalk between MM and the BM-microenvironment.

What the reader will gain: In this study we review those MM-associated molecules that have shown promising antitumor effects as targets of specific mAbs in preclinical settings, thus deserving to be considered for clinical investigation.

Take home message: mAbs directed against MM-associated adhesion markers should be taken into account in clinical practice, since they could possibly represent the best available combination of tumor cytotoxicity, environmental signal deprivation and immune system redirection.     

Elotuzumab: a novel anti-CS1 monoclonal antibody for the treatment of multiple myeloma

Background: Establishment of human osteoblast cultures that retain bone-forming capacity is one of the prerequisites for successful bone regeneration therapy. Because osteoblasts harvested from adults exhibit limited growth, the use of immature osteoblasts that can expand ex vivo should greatly facilitate bone regeneration therapy. In this study, we developed immature human osteoblasts isolated from aged alveolar bone (HAOBs).

Methods: HAOBs obtained after the collagenase digestion of alveolar bones from elderly donors. Then, we assessed osteogenic ability of HAOB after treatment with recombinant human bone morphogenic protein-2 or transplantation into immunodeficient mice. In addition, we performed global gene expression analysis to identify functional marker for HAOB.

Results: HAOBs, which can differentiate into osteoblasts and have a robust bone-forming ability, were successfully extracted from donors who were > 60 years of age. We found that the HAOBs exhibited a higher osteogenic ability compared with those of human mesenchymal stem cells and highly expressed NEBULETTE (NEBL) with osteogenic abilities.

Conclusions: HAOBs have properties similar to those of human immature osteoblasts and appear to be a novel material for cell-based bone regeneration therapy. Additionally, the expression level of NEBL may serve as a marker for the osteogenic ability of these cells.     

Lenalidomide in the treatment of multiple myeloma: a review

Lenalidomide is an immunomodulatory drug derived from thalidomide. It was developed to maximize the anti-inflammatory and anti-neoplasic properties of thalidomide and to reduce its toxicity. The molecular mechanism of action of lenalidomide is unclear, but its therapeutic activity is mainly due to its well defined anti-inflammatory, immunomodulatory, anti-proliferative and anti-angiogenic properties. In relapsed or refractory multiple myeloma (MM), lenalidomide, combined with standard dose dexamethasone, is superior to dexamethasone alone in terms of time to progression, response rate and overall survival. The most commonly reported adverse events include haematological toxicity with manageable neutropenia and thrombopenia. Lenalidomide does not trigger the limiting toxicities of thalidomide: somnolence, neuropathy and constipation. Lenalidomide, in combination with dexamethasone, is indicated for the treatment of MM patients who have received at least one prior therapy and is administered orally at the dose of 25 mg q.d. for 21 days of 28-day cycles. The drug is being investigated for the treatment of newly diagnosed MM. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical trial data on lenalidomide.     

Monoclonal antibodies currently in Phase II and III trials for multiple myeloma

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option.

Areas covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options.

Expert opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.     

Update on elotuzumab,a novel anti-SLAMF7 monoclonal antibody for the treatment of multiple myeloma

ABSTRACT

Introduction: In 2015, 4 new drugs were approved for the treatment of patients with multiple myeloma who experience drug resistance and relapsing disease, offering potential for improved patient outcomes. Given the mortality, morbidity, and projected rise in the incidence of multiple myeloma, more effective, novel therapies and treatment combinations are needed for patients at each stage of the disease.

Areas covered: Here, the authors examine published data regarding the development and clinical investigation of elotuzumab, a SLAMF7-targeted monoclonal antibody, for treatment of patients with multiple myeloma. The clinical efficacy, safety, and tolerability of elotuzumab treatment are summarized.

Expert opinion: Elotuzumab, a first-in-class immunostimulatory monoclonal antibody, is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1–3 prior therapies. Elotuzumab has the potential for use in patients in the upfront setting, in combination with other backbone regimens, as well as maintenance therapy. Trials demonstrate clinical benefit of adding elotuzumab to conventional lenalidomide and dexamethasone therapy, without additive toxicity. Data suggest that elotuzumab may provide clinical benefit in combination with proteasome inhibitors. Elotuzumab combination therapy is currently under further evaluation in the relapsed/refractory and newly diagnosed settings.     

多发性骨髓瘤患者骨损害与肝细胞生长因子血清浓度关系的探讨

目的　探讨多发性骨髓瘤(MM)患者骨损害程度与肝细胞生长因子(HGF)血清浓度的关系。方法　采 用双抗体夹心酶联免疫吸附法检测32例MM患者的HGF血清浓度,观察其与多发性骨髓瘤骨损害的关系。结果　 不同程度骨损害的MM患者,其血清HGF浓度的差异有统计学意义(P<0.01);MM骨损害越严重,其血清HGF 浓度增高越显著。结论　MM患者HGF血清浓度与骨损害程度有关,骨损害程度严重者,HGF血清浓度明显增高。     

Allogeneic stem cell transplantation in multiple myeloma: immunotherapy and new drugs

Introduction: Autologous (auto) stem cell transplantation (SCT) and the development of new drugs have improved the survival of multiple myeloma (MM) patients. By contrast, though potentially curative, the use of allogeneic (allo)-SCT is controversial.

Areas covered: A review has been conducted to examine the current evidence for the use of allo-SCT in MM. We have examined novel cell therapies that may be exploited to induce myeloma-specific immune responses including the new promising frontier of chimeric antigen receptor (CAR)-T and -natural killer (NK) cells.

Expert opinion: One of the major controversies facing researchers in exploring the allo approach is the remarkable recent treatment improvement observed with second- and third-generation proteasome inhibitors and immunomodulatory drugs, monoclonal antibodies and deacetylase inhibitors. Despite these great advances, the disease remains to be incurable and allo-SCT may still play a role in the cure of MM. We think that allo-SCT conserves a role in MM and its curative potential in high-risk patients should be explored in the setting of control clinical trials. Novel cell therapies such as CAR technologies may open new avenues of research toward a potential cure. Data from currently ongoing prospective studies will be helpful to clarify pending clinical questions.     

骨髓间充质干细胞在多发性骨髓瘤活动与缓解期具有不同的促血管生成能力

背景：活动期和缓解期多发性骨髓瘤患者骨髓间充质干细胞的血管生成能力有无差异目前尚不清楚。目的：观察多发性骨髓瘤活动期及缓解期骨髓间充质干细胞促血管生成能力的差异。方法：抽取13例多发性骨髓瘤患者治疗前和4个周期治疗后的骨髓,分离培养出骨髓间充质干细胞,采用ELISA 方法测定骨髓间充质干细胞培养上清液中血管内皮生长因子、肝细胞生长因子、碱性成纤维细胞生长因子的浓度;MTT检测骨髓间充质干细胞培养上清液对脐静脉内皮细胞增殖能力的影响;通过Transwel 小室观察骨髓间充质干细胞培养上清液对脐静脉内皮细胞运动能力的影响;通过人工基底膜实验观察骨髓间充质干细胞体外促血管生成和成管能力。结果与结论：活动期多发性骨髓瘤患者骨髓间充质干细胞培养上清中血管内皮生长因子、肝细胞生长因子、碱性成纤维细胞生长因子浓度明显高于缓解期（P〈0.05）;骨髓瘤患者骨髓间充质干细胞上清对脐静脉内皮细胞增殖作用呈剂量依赖性,活动期明显强于缓解期（P〈0.05）;活动期骨髓瘤患者骨髓间充质干细胞上清对脐静脉内皮细胞迁移作用明显高于缓解期（P〈0.05）;骨髓瘤患者骨髓间充质干细胞体外具有明显成血管作用,活动期明显强于缓解期（P〈0.05）。结果提示多发性骨髓瘤活动期骨髓间充质干细胞促血管生成能力明显大于缓解期。     

骨硬化蛋白单克隆抗体治疗骨质疏松

背景：骨硬化蛋白可负向调节骨代谢,其单克隆抗体可拮抗负向调节作用,在促进骨形成的同时抑制骨吸收。目的：旨在探讨骨硬化蛋白单克隆抗体在治疗骨质疏松中的作用机制及最新进展。方法：由第一作者应用计算机检索 PubMed、中国期刊全文数据库（CNKI）、维普数据库和万方数据库（2005年 5 月至 2013 年 5 月）相关文献。在标题、摘要、关键词中以＂osteoporosis,antibody,sclerostin,Wnt,SOST＂或＂骨质疏松,单克隆抗体,骨硬化蛋白,Wnt 通路＂为检索词进行检索。选择文章内容与骨硬化蛋白单克隆抗体有关者,同一领域文献则选择近期发表在权威杂志文章。结果与结论：初检得到 170 篇文献,根据纳入标准选择关于骨硬化蛋白单克隆抗体的 54 篇文献进行综述。骨硬化蛋白通过与 Wnt 经典信号通路共受体低密度脂蛋白受体相关蛋白 5/6 结合以阻断 Wnt 通路,从而抑制成骨细胞分化及矿化。其单克隆抗体通过与骨硬化蛋白特异性结合而间接促进骨形成、抑制骨吸收,在骨质疏松的治疗中有重大意义。同时,与其他治疗方法相比,骨硬化蛋白作用靶点的组织特异性及骨硬化蛋白单克隆抗体的结合特异性为其增加了应用优势。     

胸苷激酶1在多发性骨髓瘤治疗及预后中的临床意义

目的 探讨胸苷激酶1（TK1）在多发性骨髓瘤（MM）治疗及预后中的临床意义。方法 入选32例MM患者、20例意义未明的单克隆免疫球蛋白血症（MGUS）患者和同期20例健康人,分析3组β2微球蛋白（β2 MG）、球蛋白（GLB）、乳酸脱氢酶（LDH）和血清TK1水平差别。根据MM国际分期体系（ISS）,MM组分为Ⅰ期、Ⅱ期、Ⅲ期组,分析组间β2 MG、GLB、LDH和TK1水平差别,并对治疗前血清TK1和β2 MG、GLB、LDH水平进行相关性分析;所有MM患者均接受化疗,比较不同疗效患者治疗前后的TK1表达水平;对不同TK1水平的MM患者中位生存期进行分析,探讨TK1在MM患者治疗及预后中的意义。结果 MM组β2 MG、GLB、LDH和TK1水平高于MGUS组及健康对照组（P<0.05）;Ⅲ期的β2 MG、GLB、LDH、TK1高于Ⅰ期和Ⅱ期（P<0.05）;治疗前血清TK1水平与β2 MG、GLB、LDH呈正相关（P<0.05）;有效组治疗后的TK1表达水平下降（P<0.05）;Kaplan Meier生存曲线显示血清TK1<4.97 pmol/L的MM患者5年累积生存率为64.7%,高于血清TK1≥4.97 pmol/L的MM患者(20.0%),差异有统计学意义(P<0.05)。结论 MM患者血清TK1水平明显升高,TK1水平对治疗效果的判定有一定参考意义,并且影响预后。