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。     

B-cell maturation antigen-specific chimeric antigen receptor T cells for multiple myeloma: Clinical experience and future perspectives

Despite major advances in the treatment of multiple myeloma (MM), it remains a largely incurable disease with long-term control often dependent on continuous therapy. More effective, better tolerated treatments are therefore required to achieve durable remissions and to improve the quality of life of MM patients. Adoptive immunotherapy employing T cells expressing chimeric antigen receptors (CAR) is currently among the most promising treatment approaches in cancer. Within the target portfolio for MM immunotherapy, B-cell maturation antigen (BCMA) is among the most widely studied target antigens. BCMA is consistently expressed on MM cells and, importantly, is not expressed in critical healthy tissue. For this reason, it is an ideal target for MM immunotherapy. Several clinical trials evaluating different BCMA-targeting CAR constructs have been initiated and early results are very promising. However, in this rapidly developing clinical landscape, the ultimate role of BCMA-specific CAR-T cell therapy remains unclear. In this review, we will summarize currently available clinical data on BCMA-directed CAR-T cells and discuss potential future perspective for this promising treatment approach in MM.     

靶向B细胞成熟抗原在多发性骨髓瘤中的治疗进展

过去20年,多发性骨髓瘤（multiple myeloma,MM）的治疗取得了较大的进展,患者的生存时间获得显著延长,但多数患者最终仍会复发或变为难治性,MM仍然无法治愈。B细胞成熟抗原（B cell maturation antigen,BCMA）的表达仅限于一些B细胞谱系,在MM细胞上广泛表达,是MM的一个理想靶抗原。多种靶向BCMA的治疗,包括嵌合抗原受体（chimeric antigen receptor,CAR）T 细胞、双特异性抗体（bispecific antibodies,BsAbs）和抗体-药物偶联物（antibod-drug conjugate,ADC）,在复发/难治性MM患者中取得显著的临床反应。本文综述了近年来MM靶向BCMA治疗的研究进展。      

An Overview of CAR T Cell Mediated B Cell Maturation Antigen Therapy

Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM (Refractory/Relapsed Multiple Myeloma). BCMA (B cell maturation antigen) is primarily produced on mature B cells. It's up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell (Chimeric antigen receptor T cell) treatments, ADCs (Antibody-drug conjugate s), bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.     

CARs in the Lead Against Multiple Myeloma

The recent clinical success of CD19-directed chimeric antigen receptor (CAR) T cell therapy in chronic and acute leukemia has led to increased interest in broadening this technology to other hematological malignancies and solid tumors. Now, advances are being made using CAR T cell technology to target myeloma antigens such as B cell maturation antigen (BCMA), CD138, and kappa-light chain as well as CD19 on putative myeloma stem cells. To date, only a limited number of multiple myeloma patients have received CAR T cell therapy but preliminary results have been encouraging. In this review, we summarize the recently reported results of clinical trials conducted utilizing CAR T cell therapy in multiple myeloma (MM).     

CAR-T细胞治疗多发性骨髓瘤优化策略

多发性骨髓瘤(multiple myeloma, MM)是第二大最常见的血液系统恶性肿瘤,尽管现代疗法使患者症状得到了显著改善,整体生存率明显提高,但多数患者仍然复发并死亡。嵌合抗原受体T(chimeric antigen receptor T,CAR-T)细胞疗法在多种肿瘤治疗特别是血液系统肿瘤治疗中显示出明显疗效,为复发/难治性MM的治疗带来希望。本文主要从CAR-T细胞结构设计、活性优化、安全性控制等方面来阐述CAR-T细胞治疗MM的优化策略新进展。     

血液肿瘤CAR-T细胞治疗的现状与挑战

过继性细胞免疫疗法（adoptive cellular immunotherapy,ACI）是药物开发中一种全新模式,目前已具备在肿瘤疾病中带来临床益处的明确证据。其中嵌合抗原受体修饰的T细胞（chimeric antigen receptor-modified T cells,CAR-T）疗法利用基因工程技术重编程T细胞,使其具备非主要组织相容性抗原复合物（major histocompability complex,MHC）限制性的靶向结合并杀伤肿瘤细胞的能力,并在急性B淋巴细胞性白血病（B-cell acute lymphoblastic leukemia,B-ALL）、非霍奇金淋巴瘤（non-Hodgkin's lymphoma,NHL）、多发性骨髓瘤（multiple myeloma,MM）患者中展现出显著的缓解率,为难治复发性血液肿瘤疾病提供了治愈希望,因此多项商品化CAR-T产品也获批应用于临床,开拓了肿瘤免疫治疗的新时代。然而,细胞因子释放综合征（cytokine release syndrome,CRS）、免疫效应细胞相关神经毒性综合征（immune effector cell-associated neurotoxicity syndrome,ICANS）和其他并发症的发生是其应用的安全性挑战,并且部分患者发生CAR-T治疗无效或复发,需要提出优化CAR-T细胞疗法的新策略,在不同水平强化肿瘤清除作用,以确保安全性和有效性。本文对血液肿瘤领域的CAR-T细胞疗法临床研究进展进行综述,并归纳了下一代CAR-T细胞疗法面临的主要挑战,为拓展CAR-T细胞基础研究及临床转化研究方向提供思路。      

“Off-the-shelf” immunotherapies for multiple myeloma

Over the past couple of decades, the life expectancy of patients with multiple myeloma (MM) has progressively increased, however, the disease per se remains incurable. This has resulted in a subset of the patient population who have progressed despite multiple standard treatment options but remain amenable for novel therapies to achieve durable remission. With the discovery of the role of B-Cell Maturation Antigen (BCMA) in the pathogenesis of MM, strategies targeting the BCMA have been the focus of many treatment modalities in development. Although autologous CAR-T cell therapy has shown an overall efficacy of >80% across various phases of studies, it has its own set of limitations and challenges. There is now an increasing focus on identifying novel therapeutic targets for multiple myeloma and developing “off-the-shelf” immunotherapeutic approaches for treatment of MM. This review discusses and highlights the emerging data from various ongoing trials on “off-the-shelf” approaches like antibody-drug conjugates, bispecific antibodies, and allogeneic cellular therapies demonstrating feasibility, acceptable safety, and promising preliminary efficacy. Ongoing and future efforts will need to focus on comparative effectiveness of these different approaches, possible combination strategies, and ensuring equitable and affordable access to these therapies globally.     

SOHO State-of-the-Art Updates and Next Questions | BCMA-Directed CAR T-Cells: Early Results and Future Directions

Despite continued advances that have led to improved survival of patients with multiple myeloma (MM) over the years, MM remains largely incurable with overall survival in patients who have progressed after proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody therapy measured in months. Better understanding of the immunopathology of MM has led to the discovery of newer treatment targets like B-cell maturation antigen (BCMA). BCMA is a tumor necrosis factor receptor superfamily expressed on normal B-lymphocytes and malignant plasma cells with a vital role in proliferation, maturation, and differentiation of normal and malignant plasma cells. Antibody drug conjugates, chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers targeting the BCMA antigen are now available within and outside of clinical trials for treatment of triple class refractory MM. This review article focuses on the evolution, safety, efficacy, and limitations of BCMA-directed CAR T-cell therapies. It also discusses the challenges unveiled by the incorporation of these CAR T-cells in the treatment paradigm of MM and deliberates on the future of CAR T-cell therapy within MM.     

来那度胺联合抗B细胞成熟抗原嵌合抗原受体T细胞治疗复发难治多发性骨髓瘤一例并文献复习

目的:探讨来那度胺联合抗B细胞成熟抗原（BCMA）嵌合抗原受体T细胞（CAR-T）治疗复发难治多发性骨髓瘤（RRMM）的临床效果。方法:回顾分析河南省中医院2020年1月收治的1例接受来那度胺联合抗BCMA CAR-T治疗的RRMM患者临床资料,分析其临床特点及诊治情况,并复习相关文献。结果:患者为51岁男性,2015年10月确诊IgD-λ型多发性骨髓瘤（MM）,接受包括免疫调节剂和蛋白酶体抑制剂等方案化疗10个疗程后缓解,随后接受自体造血干细胞移植;移植后14个月MM复发,采用多种化疗方案及鼠源和人源抗BCMA CAR-T治疗,病情持续进展。用氟达拉滨和环磷酰胺预处理后,-1天服用来那度胺,次日输注人源抗BCMA CAR-T,输注后发生3级细胞因子释放综合征（CRS）,对症治疗后缓解。抗BCMA CAR-T治疗后14 d原发病评估达非常好的部分缓解（VGPR）,至截稿前已维持VGPR 3个多月。结论:来那度胺联合抗BCMA CAR-T治疗RRMM是可行的和有效的。     

Chimeric Antigen Receptor T-cell Therapy for Multiple Myeloma

Relapsed/refractory multiple myeloma (MM) remains a significant clinical challenge, despite a wide array of approved therapeutic agents. Immunotherapy offers an advantage in this setting. Chimeric antigen receptor (CAR) modified T-cells have transformed care for patients with hematologic malignancies. CAR-T cells targeting CD-19 B-cell lymphoma cells have shown prominent activity in lymphoma and acute lymphoblastic leukemia. Recently, the CAR-T cell platform for MM demonstrated therapeutic benefit. Hence, it is rapidly progressing. The most commonly tested target for MM is the B-cell maturation antigen. Complexities involved in the generation and use of CAR-T cells for MM include the identification of appropriate target antigens that are specific, and tumor type restricted, in addition to the optimization of CAR constructs to mitigate toxicities including cytokine release syndrome. CAR-T cells hold immense promise as a therapeutic modality for the treatment of MM. In this article, we provide an updated review of clinical trials of MM-specific CAR-T cells.     

Emerging Targets and Cellular Therapy for Relapsed Refractory Multiple Myeloma: A Systematic Review

Multiple myeloma is the second most common hematologic malignancy and remains incurable. Patients who fail multiple lines of therapy typically have a poor prognosis despite recent advances in myeloma treatment. Chimeric antigen receptor T (CAR T) cell treatment has emerged as a promising therapy for many hematologic malignancies, including recently approved and emerging applications for myeloma treatment. A systematic review of the available clinical trial data for CAR T therapies in multiple myeloma was undertaken. All multiple myeloma trials registered at ClinicalTrials.gov were reviewed and studies mentioning CAR T and studying relapsed/refractory multiple myeloma (R/R MM) were included. PubMed, Google Scholar, and conference proceedings were also reviewed to determine which trials had reported data. Twenty-seven registered clinical trials in humans with published data were identified as of March 10, 2021. The majority of these trials were CAR T cells targeting B-cell maturation antigen (BCMA), and many were Phase I studies. Data demonstrated promising short-term (<12 months) efficacy with low incidence of grade 3 or higher toxicities. CAR T cell therapy in R/R MM remains a promising treatment modality. While one biologic has recently received FDA-approval, the majority of products remain investigational and in early-phase trials. More investigation is needed to determine which CAR T constructs and combination therapies optimize patient outcomes.     

靶向BCMA CAR-T细胞在复发难治性多发性骨髓瘤中的治疗进展

多发性骨髓瘤（multiple myeloma,MM）是由骨髓中浆细胞恶性增殖引起的血液系统恶性肿瘤,现临床上多采取化疗、自体干细胞移植、蛋白酶体抑制剂、免疫调节药物及单克隆抗体等方法治疗,但终将复发不可治愈。复发难治性多发性骨髓瘤（relapsed/refractory multiple myeloma,R/R MM）现仍是治疗中的难题。近年来,随着嵌合抗原受体T细胞（chimeric antigen receptor T cell,CAR-T）技术的发展,靶向BCMA CAR-T治疗作为一种新型的治疗R/R MM的方法,在临床试验中获得了较高的反应率和疗效。本文将对现有的靶向BCMA CAR-T产品的最新研究进行综述。      

Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma

Multiple myeloma (MM) is an aggressive incurable plasma cell malignancy with a median life expectancy of less than seven years. Antibody‐based therapies have demonstrated substantial clinical benefit for patients with hematological malignancies, particular in B cell Non‐Hodgkin''s lymphoma. The lack of immunotherapies specifically targeting MM cells led us to develop a human‐mouse chimeric antibody directed against the B cell maturation antigen (BCMA), which is almost exclusively expressed on plasma cells and multiple myeloma cells. The high affinity antibody blocks the binding of the native ligands APRIL and BAFF to BCMA. This finding is rationalized by the high resolution crystal structure of the Fab fragment in complex with the extracellular domain of BCMA. Most importantly, the antibody effectively depletes MM cells in vitro and in vivo and substantially prolongs tumor‐free survival under therapeutic conditions in a xenograft mouse model. A BCMA‐antibody‐based therapy is therefore a promising option for the effective treatment of multiple myeloma and autoimmune diseases.     

Megakaryocyte aplastic thrombocytopeniaafter CAR T-cell therapy in a patient withmultiple myeloma:A case report

Chimeric antigen receptor(CAR)T-cell therapy is an effective new treatment strategy for hematologic malignancies.The success of CAR T-cell therapy in treating leukemia and lymphoma has promoted its development for multiple myeloma(MM),and the initial results of CAR T cell therapy have been encouraging.CAR T-cell therapy target antigens that have been clinically evaluated in MM;these antigens include CD19,B cell maturation antigen(BCMA),CD38,and CD138.A barrier to the widespread use of CAR T-cell therapy is its toxicity,primarily cytokine release syndrome(CRS),and neurologic toxicity.This study reports a patient with refractory MM who also developed megakaryocyte aplastic thrombocytopenia after receiving CAR T-cell therapy;such a case or the unusual side effects involving medications are yet unreported.There are risks in using cyclosporine and other immunosuppressants that may lead to MM recurrence as the use of such substances is contradictory to previous treatments;therefore,we temporarily administered platelet infusion as supportive care.Thus far,the condition of the patient has been steady and the patient regularly takes blood test in the hospital.     

新药时代硼替佐米在初治多发性骨髓瘤中的一线诱导治疗地位会受到挑战吗?

对于初治多发性骨髓瘤(MM)患者,以硼替佐米为基础的化疗方案获得了较高的完全缓解率、较长的无进展生存及总生存,其在可移植及非可移植患者中均具有一线诱导治疗地位.近年来,新型药物(如蛋白酶体抑制剂、免疫调节剂、单克隆抗体及细胞免疫疗法等)由于具有较好的疗效和安全性,对硼替佐米的一线治疗地位提出了挑战.口服蛋白酶体抑制剂联合免疫调节剂和地塞米松、单克隆抗体联合免疫调节剂和地塞米松未来有望成为初治MM患者的一线诱导治疗方案.在更远的将来,嵌合抗原受体T细胞免疫疗法(CAR-T)也可能成为一线治疗的一部分,尤其是用于高危患者的诱导或清除微小残余病变的巩固治疗.     

多发性骨髓瘤的新药研发与治疗现状

近20年来，多发性骨髓瘤（multiple myeloma，MM）治疗领域出现了划时代的进步。随着免疫调节剂（immunomodulatory drugs，IMiDs）、蛋白酶体抑制剂（proteasome inhibitors，PIs）的出现和普及，患者的治疗疗效明显提高，生存期显著延长，上述两类药物以及自体造血干细胞移植（autologous stem cell transplantation，ASCT）已成为MM治疗的基石。同时，新的药物仍在不断涌现。如新一代的IMiDs、PIs，抗体类药物及其衍生药物及小分子靶向性治疗药物，还出现了嵌合抗原受体T细胞免疫治疗（chimeric antigen receptor T-cell immunotherapy，CAR-T）等手段。上述治疗在MM中均显示出良好的前景。本文旨在对MM领域新药的研发和应用进行综述。      

CAR-T细胞治疗多发性骨髓瘤的研究进展

多发性骨髓瘤（MM）是一种源于骨髓浆细胞的恶性肿瘤,截止目前尚无有效的治愈手段。嵌合抗原受体(CAR)-T细胞疗法是一种具有广阔研究前景的MM治疗方法。其设计理念是通过对部分基因序列进行特异性的改造,使CAR特异性地影响靶向肿瘤细胞的抗原,受体与抗原相结合以激活T细胞杀死肿瘤细胞。本文主要阐述CAR-T细胞疗法的设计过程、研究进展及现阶段所面临的缺陷。     

多发性骨髓瘤诊断与治疗:现状与挑战

过去的十年中,国内外多发性骨髓瘤(MM)的发病机制、危险分层以及治疗等方面的研究取得了突破性进展.新药的不断出现、嵌合抗原受体重定向T细胞的问世以及异基因造血干细胞移植的开展,使MM患者预后得到了极大改善.     

CAR T-cell therapy in multiple myeloma: more room for improvement

The emergence of various novel therapies over the last decade has changed the therapeutic landscape for multiple myeloma. While the clinical outcomes have improved significantly, the disease remains incurable, typically in patients with relapsed and refractory disease. Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable clinical success in B-cell malignancies. This scope of research has more recently been extended to the field of myeloma. While B-cell maturation antigen (BCMA) is currently the most well-studied CAR T antigen target in this disease, many other antigens are also undergoing intensive investigations. Some studies have shown encouraging results, whereas some others have demonstrated unfavorable results due to reasons such as toxicity and lack of clinical efficacy. Herein, we provide an overview of CAR T-cell therapies in myeloma, highlighted what has been achieved over the past decade, including the latest updates from ASH 2020 and discussed some of the challenges faced. Considering the current hits and misses of CAR T therapies, we provide a comprehensive analysis on the current manufacturing technologies, and deliberate on the future of CAR T-cell domain in MM.Subject terms: Cancer immunotherapy, Translational research, Myeloma