树突细胞疫苗用于多发性骨髓瘤的免疫疗法

多发性骨髓瘤(MM)是一种浆细胞恶性增生性疾病,其独特型是一种肿瘤特异性抗原.该病的发病率呈上升趋势,而传统治疗对其效果不佳.借助树突细胞(DC)强大的抗原递呈功能结合独特型制备疫苗,可在体内外活化CD4+、CD8+T细胞,从而激发特异性抗肿瘤效应.为多发性骨髓瘤的免疫治疗提供了新方法.     

肿瘤基因与分子疫苗的研究现状及进展

肿瘤疫苗免疫治疗是利用肿瘤抗原进行主动免疫来激发、增强机体对肿瘤的主动特异性免疫反应.目前所研究的肿瘤疫苗主要是基因工程疫苗、肽疫苗、核酸疫苗、抗独特型抗体疫苗.     

抗独特型抗体与肿瘤免疫治疗

抗独特型抗体的应用是近年来肿瘤免疫治疗的一种新方法，抗独特型抗体由特异性抗体Ab1诱导产生，具有替代抗原作用，能诱导机体产生特异性的免疫应答。大量的动物实验和临床资料表明，肿瘤特异性独特型瘤苗具有较多的优点和较强的抗瘤作用。本文对其产生特异免疫反应和抗瘤作用的机制进行了探讨，并根据国外最新研究动态，综述了独特型抗体在主动免疫治疗方面的实验资料及对几种肿瘤的治疗价值。     

抗独特型抗体在肿瘤主动免疫治疗研究中的进展

抗独特型抗体具有模拟抗原及免疫调节双重作用，能代替肿瘤抗原，诱发特异性免疫反应，临床初步应用显示出一定疗效。本文对抗独特型抗体及其在肿瘤主动免疫治疗研究中的进展作一综述。     

B细胞淋巴瘤的抗独特型免疫治疗

 引言随着对肿瘤免疫机制的不断了解 ,肿瘤的免疫治疗逐渐成为人们研究的热点。寻找能够有效激发机体免疫反应的肿瘤特异性抗原是进行免疫治疗的关键。B细胞淋巴瘤在此方面有着特殊的优势 ,表达于B细胞表面的免疫球蛋白 (Ig)可变区的独特型(idiotype ,Id)可作为肿瘤特异性抗原 ,诱导产生抗独特型抗体和 /或激活T细胞介导的细胞免疫 ,从而用于免疫治疗。本文将对B淋巴瘤的抗独特型免疫治疗作一简要综述。1　B细胞淋巴瘤的免疫学特点大多数B细胞肿瘤都是单个克隆的B细胞恶性扩张所致。肿瘤细胞表面表达的Ig分子的可变区具有其独特的构象 ,称为独特型 ,他们既可作为抗原识别受体 ,同时也可作为抗原被其特异性抗体识别。Ig编码基因的重排和体细胞突变决定了Ig具有多样性 ,使其成为每个B细胞克隆特有的标志。因此当发生某个B细胞克隆恶变后异常增生 ,其独特型就可作为肿瘤特异性抗原 ,通过诱导产生抗独特型的抗体和 /或激活T细胞介导的细胞免疫有可能达到治疗效果。以往对独特型的研究重点主要在其互补决定区 (complementaritydeterminingre gions ,CDR区 ) ,近年来 ,许多研究表明框架区(f...     

多发性骨髓瘤抗独特型决定簇免疫治疗研究进展

传统疗法通常无法治愈多发性骨髓瘤(MM),近年来提出了用于提高长期生存率的免疫治疗方法.其中,对于已经接受大剂量化疗以及自体或异体干细胞移植的MM患者,通过使用树突细胞(DC)介导的抗独特型决定簇瘤苗进行免疫治疗的体内研究结果证实,独特性抗肿瘤效应的产生能够有效根除微小残留病变,明显延长患者的无病生存期.现综述MM抗独特型决定簇(Id)治疗性瘤苗、细胞瘤苗以及基因疫苗的相关临床和临床前研究进展.     

卵巢癌抗独特型单链抗体6B11ScFv/鼠GMCSF融合蛋白(6B11mGM)的构建、表达和特性研究

抗独特型抗体能够模拟肿瘤抗原,调节机体免疫功能,已成为肿瘤免疫治疗研究中一个十分重要的研究领域.本中心制备的卵巢癌抗独特型抗体6B11能模拟卵巢癌抗原诱导特异性抗肿瘤免疫应答.为降低鼠源性单抗进入体内引起的不良免疫反应,本中心已成功制备了基因工程抗独特型单链抗体(6B11ScFv).为了增加6B11ScFv的免疫原性,又构建了6B11ScFv与人GM-CSF融合蛋白(6B11GM).但由于缺     

肿瘤特异性主动免疫治疗的现状与进展

肿瘤的特异性主动免疫治疗已经过近一个世纪的研究。近年来，各种肿瘤疫苗，尤其是病毒疫苗，癌基因疫苗，多肽疫苗和独特型疫苗的研究均取得可喜进展，其诱导机体特异性坟动免疫应答，增强机体抗瘤能力的作用在动物实验中已得到肯定，许多疫苗已进入临床试验研究，是一种有广阔应用前景的肿瘤免疫治疗方法     

多发性骨髓瘤抗独特型决定簇免疫治疗研究进展

传统疗法通常无法治愈多发性骨髓瘤(MM)，近年来提出了用于提高长期生存率的免疫治疗方法。其中，对于已经接受大剂量化疗以及自体或异体干细胞移植的MM患者，通过使用树突细胞(DC)介导的抗独特型决定簇瘤苗进行免疫治疗的体内研究结果证实，独特性抗肿瘤效应的产生能够有效根除微小残留病变，明显延长患者的无病生存期。现综述MM抗独特型决定簇(Id)治疗性瘤苗、细胞瘤苗以及基因疫苗的相关临床和临床前研究进展。     

多发性骨髓瘤的免疫治疗研究进展

免疫治疗是最有希望控制和清除微小残留病(MRD)从而治愈多发性骨髓瘤(MM)的治疗方法。动物模型和临床实验研究显示MM的免疫治疗尤其是以免疫接种为基础的主动免疫具有巨大的应用潜力。对3种主要的免疫接种策略：肿瘤特异性抗原疫苗、DC树突细胞介导的免疫治疗和瘤苗在MM治疗中的研究进展加以综述。     

Immunotherapy of multiple myeloma: the start of a long and tortuous journey

The field of tumor immunotherapy is still in its infancy. It is becoming clear that the human immune response is the result of highly complex, continuously evolving interactions between cells of the adaptive and innate arms of the immune system, the internal and external environments, and normal and abnormal cells (e.g., myeloma plasma cells). Despite the considerable advances in our knowledge over the past 30 years, we have still only scratched the surface of the immune system’s interaction with malignant diseases such as myeloma and to date, this has not translated into significantly better outcomes for patients with this disease. This review will summarize our current knowledge of the fundamental immunology of myeloma, review immunotherapy trials reported to date and discuss whether, in light of the current information, immunotherapy of multiple myeloma is an achievable goal.     

Immunotherapy of multiple myeloma: the start of a long and tortuous journey

The field of tumor immunotherapy is still in its infancy. It is becoming clear that the human immune response is the result of highly complex, continuously evolving interactions between cells of the adaptive and innate arms of the immune system, the internal and external environments, and normal and abnormal cells (e.g., myeloma plasma cells). Despite the considerable advances in our knowledge over the past 30 years, we have still only scratched the surface of the immune system's interaction with malignant diseases such as myeloma and to date, this has not translated into significantly better outcomes for patients with this disease. This review will summarize our current knowledge of the fundamental immunology of myeloma, review immunotherapy trials reported to date and discuss whether, in light of the current information, immunotherapy of multiple myeloma is an achievable goal.     

多发性骨髓瘤的免疫治疗研究进展

多发性骨髓瘤是血液系统恶性肿瘤,该病的复发及难治一直是一项难题。越来越多的研究发现免疫失调是骨髓瘤细胞逃避免疫监视、导致疾病发生发展的关键因素,因此免疫治疗为多发性骨髓瘤的治疗带来了很大的前景。其中一些免疫疗法已在临床应用中取得较好的治疗效果,一些仍在试验研究中的疗法也显示出巨大的治疗潜力。本文结合相关文献对免疫治疗中的免疫调节剂、靶向B细胞成熟抗原疗法的研究进展进行综述。     

Current clinical and laboratory strategies to augment the efficacy of immunotherapy in multiple myeloma.

Multiple myeloma is still an incurable, lethal disease for the vast majority of patients. Myeloablative chemotherapy combined with autologous or allogeneic hematopoietic stem cell transplantation only partially met the great expectations initially set in its efficacy and is associated with a high level of toxicity. However, the considerable progress in understanding the biology of multiple myeloma led to the development of promising molecular therapies. Numerous immunotherapy-based approaches are currently evaluated in clinical trials. Moreover, remarkable progress has been achieved in gene therapy during the last decade, and the repertoire of gene transfer techniques can be expected to improve continuously. Gene transfer is increasingly applied in biological therapies in multiple myeloma. This article reviews the currently applied clinical and laboratory strategies to augment the efficacy of immunotherapy in multiple myeloma and aims to define its perspectives in multimodality treatment of multiple myeloma.     

Dendritic cell-based immunotherapy in multiple myeloma

Most patients with multiple myeloma (MM) cannot be cured with currently available therapies. Although complete remission could be achieved in about 50% of newly diagnosed patients with high-dose chemotherapy and tandem transplantation, relapses of the underlying disease occur frequently. To realize long-term disease-free survival, it will be necessary to develop complementary therapies that are non-cross-resistant with chemotherapy. To this end, immunotherapy aimed at inducing or enhancing tumor-specific immunity that may control or eradicate remaining tumor cells may be an appealing method. Dendritic cells (DCs) are professional antigen-presenting cells and considered the best natural adjuvants for immunotherapy in malignancies. Vaccination with tumor antigen-pulsed DCs has been shown to be protective and therapeutic in animal tumor models, and induced a strong tumor-specific immunity and durable tumor regression in human solid tumors and B-cell lymphoma. As a result, clinical trials in various human malignancies have been initiated. This review will focus on DC-based immunotherapy in MM. I will discuss myeloma antigens and antigen-specific immune responses, the capacity of DCs to present myeloma antigens and induce cytotoxic T-cell responses, and clinical experience of DC vaccination in myeloma patients.     

多发性骨髓瘤免疫治疗进展

嵌合抗原受体T细胞(CAR-T)和新型靶向治疗等生物免疫疗法的临床应用开辟了多发性骨髓瘤(MM)治疗的新领域。靶向B细胞成熟抗原(BCMA)、同种异体CAR-T、抗体偶联药物(ADC)及靶向BCMA的双特异性抗体在多项临床研究中获得了令人瞩目的疗效及较好的安全性。文章结合第62届美国血液学会(ASH)年会的相关报道对MM免疫治疗进展进行介绍。     

Multiple myeloma,high-dose treatment and autologous stem cell transplantation—current status

High-dose chemo-radiotherapy with autologous stem cell transplantation (ASCT) has introduced the concept of complete remission for multiple myeloma, and can improve survival and life quality for selected groups of myeloma patients. A number of prognostic factors have been identified, where ASCT in early disease, i.e. as part of front-line treatment, seems to be of particular importance for a favourable outcome. Even so, most myeloma patients will not be cured by high-dose therapy, but new strategies such as repeated autografting and post-graft alpha-inter-feron maintenance treatment seem to add additional advantages with respect to survival and freedom of disease progression. The technical development has enabled efficientin vitro myeloma cell depletion of the autograft as well as highly sensitive detection of minimal residual disease after treatment, but the clinical significance of these issues remains to be determined, and this question is addressed in ongoing gene marking studies. The application of novel therapeutic principles, e.g. gene therapy and immunotherapy, might further ameliorate the outcome for patients with multiple myeloma.     

Activated marrow-infiltrating lymphocytes effectively target plasma cells and their clonogenic precursors

A major limitation of adoptive immunotherapy is the availability of T cells specific for both terminally differentiated tumor cells and their clonogenic precursors. We show here that marrow-infiltrating lymphocytes (MILs) recognize myeloma cells after activation with anti-CD3/CD28 beads with higher frequency than activated peripheral blood lymphocytes from the same patients. Furthermore, activated MILs target both the terminally differentiated CD138+ plasma cells and the myeloma precursor as shown by profound inhibition in a tumor clonogenic assay. The presence of antigen in the marrow microenvironment seems to be important for the maintenance of tumor specificity. Taken together, these results highlight the intrinsic tumor specificity of MILs and describe a novel approach for the generation of tumor-specific T-cell populations suitable for adoptive immunotherapy of multiple myeloma.     

Latest advances and current challenges in the treatment of multiple myeloma

Effectively treating patients with multiple myeloma is challenging. The development of therapeutic regimens over the past decade that incorporate the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has been the cornerstone of improving the outcome of patients with myeloma. Although these treatment regimens have improved patient survival, nearly all patients eventually relapse. Our improved understanding of the biology of the disease and the importance of the microenvironment has translated into ongoing work to help overcome the challenge of relapse. Several classes of agents including next-generation proteasome inhibitors, immunomodulatory agents, selective histone-deacetylase inhibitors, antibody and antitumor immunotherapy approaches are currently undergoing preclinical and clinical evaluation. This Review provides an update on the latest advances in the treatment of multiple myeloma. In particular, we focus on novel therapies including modulating protein homeostasis, kinases inhibitors, targeting accessory cells and cytokines, and immunomodulatory agents. A discussion of the challenges associated with these therapeutic approaches is also presented.     

NY-ESO-1 immunotherapy for multiple myeloma

Most patients with poor-prognosis myeloma (abnormal metaphase cytogenetics) achieve excellent responses with tandem transplants, but the remissions are not durable. Novel interventions such as immunotherapy may eradicate the residual chemotherapy-resistant disease. Immunotherapy targeting weak antigens such as myeloma idiotype or tumor lysate has failed to produce clinically meaningful responses. We previously reported that the NY-ESO-1 antigen is expressed in >60% of poor-prognosis myeloma at diagnosis. Since NY-ESO-1 is highly immunogenic and is not expressed in most normal tissues, it is an ideal target for anti-myeloma immunotherapy. NY-ESO-1 based therapies are already being tested in clinical trials for a multitude of tumors. This review discusses the potential of NY-ESO-1 immunotherapy to improve outcome for myeloma.