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。     

靶向B细胞成熟抗原的嵌合抗原受体T细胞的构建及其对肿瘤细胞的杀伤

[摘要] 目的：探索通过嵌合抗原受体（chimeric antigen receptor,CAR）-T 细胞靶向B 细胞成熟抗原（B cell maturation antigen,BCMA）以治疗多发性骨髓瘤（multiple myeloma,MM）的方法。方法：构建基于鼠源BCMA scFv 的CAR-BCMA分子,包装为慢病毒载体并感染健康人T 细胞构建CAR-BCMA-T 细胞;构建BCMA阳性细胞系A549-BCMA、A549-BCMAOFP和K562-BCMA作为靶细胞。将CAR-BCMA-T细胞与构建的靶细胞和人骨髓瘤细胞U266 共孵育,CCK-8 法和流式细胞术检测其对BCMA阳性肿瘤细胞的杀伤能力。构建MM患者来源CAR-BCMA-T细胞并检测其杀伤靶细胞A549-BCMA的能力,并采用ELISA和流式细胞术检测CAR-BCMA-T细胞IFN-γ 的释放水平。结果：健康人来源的CAR-BCMA-T经过11 d 培养扩增300 倍,阳性率达到43%;成功构建BCMA阳性靶细胞。在5:1 效靶比下,CAR-BCMA-T对A549-BCMA、K562-BCMA和U266 细胞的杀伤率分别在80%、60%和80%左右,显著高于对BCMA阴性细胞的杀伤率,且杀伤力与靶细胞的BCMA表达强度相关。在效靶比20:1 时,MM患者来源CAR-BCMA-T细胞对靶细胞A549-BCMA的杀伤率达到95%以上,并且大量分泌IFN-γ。结论：本研究成功构建了健康人及MM患者来源的靶向BCMA的CAR-T细胞,其能够有效特异杀伤BCMA阳性的肿瘤细胞。     

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。      

靶向B细胞成熟抗原的嵌合抗原受体T细胞治疗自体造血干细胞移植后复发多发性骨髓瘤3例并文献复习

目的探讨靶向B细胞成熟抗原(BCMA)的嵌合抗原受体T细胞(CAR-T)治疗自体造血干细胞移植后复发多发性骨髓瘤(MM)患者的疗效及安全性。方法回顾性分析2019年7月至2022年1月解放军联勤保障部队第九六〇医院收治的接受靶向BCMA的CAR-T治疗自体造血干细胞移植后复发MM的3例患者临床资料,并复习相关文献。结果3例MM患者移植后复发时骨髓浆细胞分别为23.5%、6.5%、34.5%。经过靶向BCMA的CAR-T治疗,3例均达到完全缓解(CR),均出现细胞因子释放综合征(CRS),其中1例为1级CRS,2例为2级CRS。3例患者输注CAR-T后,CAR-T均出现扩增及细胞因子的变化。1例在CAR-T治疗后30个月时疾病再次复发,2例仍处于持续CR状态。结论靶向BCMA的CAR-T对自体造血干细胞移植后复发的MM患者具有较好疗效和安全性。     

BCMA CAR-T细胞治疗的耐药机制及优化策略研究

嵌合抗原受体T细胞（chimeric antigen receptor T cells,CAR-T）疗法在血液系统肿瘤治疗中已展示出卓越成效。BCMA抗原在骨髓瘤细胞表面普遍表达,是合适高效的CAR-T治疗靶抗原。尤其是对于复发/难治性多发性骨髓瘤患者,BCMA CAR-T细胞治疗缓解率高,多数患者在输注1年后仍可在体内检测到CAR-T细胞。但是耐药与疾病复发仍是目前临床管理中面对的关键问题。本文将从多发性骨髓瘤细胞免疫逃逸、CAR-T产品因素、既往治疗方案及肿瘤免疫微环境的抑制等几个方面来探讨BCMA CAR-T细胞疗法的应答响应因素及耐药诱导机制,并提出可能的优化策略,以期为未来探索提供参考意义。     

靶向CD19和BCMA的CAR-NK92MI细胞的构建及抗肿瘤活性研究

目的:探讨嵌合抗原受体(chimeric antigen receptor,CAR)结构对CAR-NK细胞特异性杀伤能力的增强情况.方法:利用逆转录病毒载体分别构建出稳定表达靶向B细胞成熟抗原(B cell maturation antigen,BCMA)与分化群抗原19(cluster of differentiat...     

双特异性抗体治疗复发难治多发性骨髓瘤研究进展

近年来, 包括靶向B细胞成熟抗原(BCMA)×CD3和G蛋白偶联孤儿受体C类第5组成员D(GPRC5D)×CD3在内的双特异性抗体(BsAb)用于治疗复发难治多发性骨髓瘤(RRMM)患者进行了广泛的研究。新药Teclistamab(BCMA×CD3)于2022年成为首个获得美国食品药品管理局(FDA)批准治疗RRMM的BsAb, 埃纳妥单抗(Elranatamab)也于2023年获得批准。靶向BCMA×CD3的BsAb包括Alnuctamab、WVT078、ABBV-383、Linvoseltamab和F182112以及靶向GPRC5D×CD3的Talquetamab和LBL-034目前正在临床试验中进行评估。结合第65届美国血液学会年会报告, 对BsAb治疗RRMM的研究进展进行报道。     

双特异性抗体治疗多发性骨髓瘤研究进展

多发性骨髓瘤(MM)是一种浆细胞恶性增殖性疾病。尽管随着免疫调节剂、蛋白酶体抑制剂等靶向新药及自体造血干细胞移植疗法的广泛应用, MM患者的预后明显改善, 但疾病仍会复发进展。近年来免疫治疗在MM治疗领域取得了突破性进展, 嵌合抗原受体T细胞疗法、抗体偶联药物及双特异性抗体在疾病的不同阶段均展现了显著的有效性和良好的安全性。双特异性抗体能同时结合T细胞上的CD3和恶性浆细胞表面的靶分子, 是复发难治MM患者有效的免疫治疗药物。文章结合第64届美国血液学会年会报道对双特异性抗体治疗MM的研究进展进行总结。     

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。     

治疗B细胞非霍奇金淋巴瘤双特异性抗体的特征、疗效及安全性

B细胞非霍奇金淋巴瘤（B cell non-Hodgkin lymphoma,B-NHL）的免疫治疗在过去的20余年中经历了显著的变革,从单克隆抗体和抗体结合型药物,到嵌合抗原受体T细胞（chimeric antigen receptor T cell,CAR-T）免疫治疗和以及CD19-CD3和CD20-CD3的双特异性抗体（bispecific antibodies,BsAb）。BsAb可以同时靶向B细胞和激活细胞毒性T细胞,较单克隆抗体具有更好的疗效。与CAR-T相比,BsAb无须进行个体化的体外制备,给药方便。BsAb在复发难治的B-NHL中已显示了很好的疗效和安全性。文章着重介绍5种治疗B-NHL的BsAb的结构特点、疗效及安全性结果。     

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.     

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.     

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).     

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.     

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.     

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.     

Cytomegalovirus Retinitis and Retinal Detachment following Chimeric Antigen Receptor T Cell Therapy for Relapsed/Refractory Multiple Myeloma

Cytomegalovirus (CMV) retinitis is a rare end-organ disease of CMV infection and is a marker of severe immunosuppression, especially in human immunodeficiency virus (HIV)-positive patients. In multiple myeloma (MM) patients, CMV retinitis has been reported in the post-transplant setting, with an incidence lower than 0.2%, and in patients receiving lenalidomide. Here, we describe the first case of CMV retinitis in myeloma patients following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (BCMA CAR-T) cell therapy. In addition to CMV, the patient developed multiple infections including a mouth ulcer, pneumonia, and fungal enteritis. While the complete remission (CR) status of MM was maintained, he regained a visual acuity of 20/1000 after appropriate ophthalmologic treatment. This single case illustrates the potential of BCMA CAR-T therapy to induce profound humoral immunosuppression, and demonstrates an imperative need for an established standard of monitoring and prophylaxis of post-CAR-T infections.     

The Role of B-Cell Maturation Antigen in the Biology and Management of,and as a Potential Therapeutic Target in,Multiple Myeloma

B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab–drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs. Additionally, there are now three bispecific antibodies in development, which bind to both BCMA and CD3ε on T-cells. This latter binding results in T-cell recruitment and activation, causing target cell lysis. More recently, T-cells have been genetically engineered to recognize BCMA-expressing cells and, in 2013, the first report of anti-BCMA-chimeric antigen receptor T-cells showed that these killed MM cell lines and human MM xenografts in mice. BCMA is also solubilized in the blood (soluble BCMA [sBCMA]) and MM patients with progressive disease have significantly higher sBCMA levels than those responding to treatment. sBCMA circulating in the blood may limit the efficacy of these anti-BCMA-directed therapies. When sBCMA binds to B-cell activating factor (BAFF), BAFF is unable to perform its major biological function of inducing B-cell proliferation and differentiation into Ab-secreting PC. However, the use of γ-secretase inhibitors, which prevent shedding of BCMA from PCs, may improve the efficacy of these BCMA-directed therapies.

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