嵌合抗原受体T细胞疗法治疗多发性骨髓瘤的研究进展

多发性骨髓瘤(multiple myeloma, MM)是由浆细胞恶性增殖引起的恶性肿瘤, 可在骨髓中积累导致骨髓衰竭。MM的治疗通常包括免疫调节剂和造血干细胞移植等方式, 但是疗效并不理想。嵌合抗原受体T细胞疗法是近年来出现的一种新型免疫疗法, 通过体外基因编辑技术改造患者的T细胞, 使其能够特异性识别肿瘤细胞的表面抗原, 从而达到靶向杀伤肿瘤细胞的目的。此文主要就嵌合抗原受体T细胞在MM治疗中的应用及靶点作一介绍。     

靶向B细胞成熟抗原的多发性骨髓瘤在研新药——GSK2857916

多发性骨髓瘤(multiple myeloma, MM)是继非霍奇金淋巴瘤后第二种常见的血液系统恶性肿瘤。B细胞成熟抗原(B-cell maturation antigen, BCMA)是浆细胞存活所需的肿瘤坏死超家族的细胞表面受体,在MM患者的骨髓瘤细胞中能普遍检测到,其已被多种新型靶向疗法作为选择性抗原。GSK2857916是由葛兰素史克公司正在开发的一种新型抗体偶联药物,由抗BCMA单克隆抗体与微管蛋白聚合抑制剂单甲基尿嘧啶F缀合而成,对复发/难治性多发性骨髓瘤细胞具有良好的抑制活性。GSK2857916已被美国食品药品监督管理局授予突破性药物资格,同时被列为2019年全球最具市场潜力的在研新药之一,有望弥补这个领域的空白。本文就GSK2857916的基本信息、作用机制和临床试验情况作一概述。     

嵌合抗原受体T细胞相关脑病综合征1例并文献复习

<正>多发性骨髓瘤(multiple myeloma,MM)是一种常见的恶性浆细胞克隆性增殖性肿瘤^[1]，老年人多发，尚不可完全治愈。近年来，虽然蛋白酶体抑制剂、免疫调节剂和自体干细胞移植等治疗手段的应用显著改善了MM患者的预后^[2-3]，但仍有多数患者演变为复发/难治性多发性骨髓瘤(relapsed/refractory multiple myeloma,R/R MM)^[4]，特别是高危MM患者复发时间会更短。嵌合抗原受体修饰T细胞(chimeric antigen receptor T cell,CAR-T)是R/R MM的重要治疗手段。随着CAR-T临床试验研究进展和成果的取得^[5],CAR-T细胞作为骨髓瘤常规治疗手段指日可待。然而对CAR-T治疗的相关毒副反应未引起足够的重视。本文报道1例高危多发性骨髓瘤经CAR-T治疗后并发CAR-T细胞相关性脑病综合征(CAR-T cell-related encephalopathy syndrome,CRES)的诊疗经过，期望通过病例报...     

冒烟型多发性骨髓瘤合并干燥综合征和肺结核1例并文献复习

<正>1980年,Kyle等[1]首先发现6例符合多发性骨髓瘤(multiple myeloma,MM)诊断标准,但没有多发性骨髓瘤相关临床症状,未接受任何化疗,5年以上疾病仍处于稳定状态的患者,将其命名为冒烟型多发性骨髓瘤(smoldering multiple myeloma,SMM)。意义不明的单克隆球蛋白血症(monoclonal gammopathy of unknown significance,MGUS)也是一种无症状的浆细胞病,MGUS及SMM均是一种老年性疾病,50     

多发性骨髓瘤靶向新药有望加速上市

近日,CT053全人抗B细胞成熟抗原(BCMA)自体CAR-T细胞注射液,通过了国家药品监督管理局药品审评中心的公示期,纳入“突破性治疗药物品种”,拟定适应证为复发难治性多发性骨髓瘤。纳入突破性治疗药物程序,有望加速这款新药在中国的研发和审批速度,更早惠及国内患者。多发性骨髓瘤是一种克隆性浆细胞异常增殖的恶性疾病,复发难治性多发性骨髓瘤尤甚。肿瘤免疫治疗近年来发展很快,CAR-T细胞治疗是其中一条技术路线。T淋巴细胞具有免疫活性,如同人体内的特种部队,专门杀灭外来入侵者。     

Ciltacabtagene autoleucel——治疗复发难治性多发性骨髓瘤的靶向BCMA CAR-T细胞新型疗法

2022年2月28日,美国食品和药物管理局(FDA)批准Ciltacabtagene autoleucel(Cilta-cel)上市,用于治疗成人复发难治性多发性骨髓瘤(relapsed or refractory multiple myeloma, RRMM)。Cilta-cel是中国首个获FDA批准的细胞治疗产品,亦是全球第二款获批靶向B细胞成熟抗原(B-cell maturation antigen, BCMA)的嵌合抗原受体(chimeric antigen receptor, CAR)-T细胞免疫疗法。最新研究发现,RRMM患者接受Cilta-cel治疗后,总缓解率(overall remission rate, ORR)高达97%,12个月无进展生存率为77%;常见毒性作用包括中性粒细胞减少、血小板减少、贫血、细胞因子释放综合征(cytokine release syndrome, CRS)及神经毒性等。本文将对Cilta-cel的作用机制、适应症、药代动力学、临床研究及不良反应等作一综述。     

嵌合抗原受体T细胞免疫疗法治疗多发性骨髓瘤的研究进展

免疫疗法在恶性肿瘤治疗中的应用正日益受到关注.嵌合抗原受体(CAR)技术是一种新兴的免疫疗法,在血液肿瘤的治疗上具有巨大的潜力.嵌合抗原受体T细胞免疫疗法(CAR-T)可通过特异性识别靶抗原来杀伤骨髓瘤细胞,使治疗复发难治性多发性骨髓瘤成为可能.该文重点对CAR-T在多发性骨髓瘤治疗方面的研究进展作一综述,并对可能作为CAR-T治疗多发性骨髓瘤的靶抗原进行了分析.     

XPO1抑制剂塞利尼索治疗多发性骨髓瘤的研究进展

多发性骨髓瘤(Multiple myeloma, MM)是目前仍无法治愈的血液系统恶性疾病,绝大多数患者会对现有治疗药物耐药,最终进展为复发/难治性多发性骨髓瘤(Relapsed/refractory multiple myeloma, RRMM),因此新药的研发及应用意义重大。选择性核输出蛋白抑制剂可通过阻断核输出蛋白1(Exportin1,XPO1),以多种途径促进MM细胞凋亡、增加MM细胞对化疗的敏感性,对RRMM患者表现出良好疗效。本文主要对XPO1抑制剂塞利尼索(Selinexor)治疗MM的研究进展进行综述。     

BCL2抑制剂治疗复发难治性多发性骨髓瘤的研究进展

多发性骨髓瘤(Multiple myeloma, MM)是浆细胞克隆性增殖的恶性血液系统疾病,尽管现在其治疗已经取得巨大治疗进展,但仍不可治愈。维奈克拉(Venetoclax, VEN)是一种选择性抗凋亡蛋白B细胞淋巴瘤因子-2(B-cell lymphoma-2,BCL-2)抑制剂,可诱发MM细胞的死亡,对携带t(11;14)易位的复发难治性多发性骨髓瘤(Relapsed and refractory multiple myeloma, RRMM)患者治疗效果好。VEN最常见的不良反应包括血细胞减少和胃肠道反应。VEN单药及联合使用对于提高RRMM的疗效具有重要影响。本文对VEN的基础实验、临床试验及真实世界研究进行简单概述。     

多发性骨髓瘤实验室检测方法分析与评价

<正>多发性骨髓瘤(multiple myeloma,MM)是一种单克隆B淋巴细胞恶性增殖的浆细胞恶性肿瘤,由于骨髓中恶性浆细胞过度增殖,导致血清或尿液中出现单克隆性免疫球蛋白或单克隆轻链的一种血液系统恶性疾病。血清游离轻链(serum free light chain,sFLC)检测是机体是否存在克隆性细胞的高度敏感的指标,已在中国多发性骨髓瘤诊治指南~([1])中更新,指南已经把sFLC检测作为诊断和     

Construction and stable gene expression of AGR2xPD1 bi-specific antibody that enhances attachment between T-Cells and lung tumor cells,suppress tumor cell migration and promoting CD8 expression in cytotoxic T-cells

There has been a substantial and consistent rise in the number of clinical trials to develop advanced and potent bispecific antibodies (BsAb) over the past two decades with multiple targets to improve the efficacy or tissue specificity of monoclonal antibodies (mAb) treatment for diseases with multiple determining factors or widely-expressed targets. In this study, we designed and synthesized BsAb AGR2xPD1 targeting extracellular AGR2, a paracrine signal, and PD1, an immune checkpoint protein. Our design is intended to use AGR2 binding to guide PD1 targeting for AGR2⁺cancer. We used this construction to produce AGR2xPD1 BsAb by generating clonally selected stable 293F cell line with high expression. Applying this BsAb in a T cell-Tumor cell co-culture system showed that targeting both PD1 and AGR2 with this BsAb induces the attachment of TALL-104 (CD8⁺ T-lymphocytes) cells onto co-cultured H460 AGR2⁺ Lung tumor cells and significantly reduces migration of H460 cells. T-cell expression of CD8 and IFNγ is also synergistically enhanced by the AGR2xPD1 BsAb treatment in the AGR2⁺H460 co-culture system. These effects are significantly reduced with AGR2 expression negative WI38 cells. Our results demonstrate that the AGR2xPD1 BsAb could be a potential therapeutic agent to provide better solid tumor targeting and synergetic efficacy for treating AGR2+ cancer by blocking AGR2 paracrine signaling to reduce tumor survival, and redirecting cytotoxic T-cells into AGR2+ cancer cells.     

Folate-mediated targeting of T cells to tumors

Recently various strategies have been developed to exploit in a clinical setting the well established finding that T cells can specifically recognize and destroy tumor cells. Several independent approaches to the targeting of T cells against cancer have been explored, including the use of bispecific antibodies (anti-T cell/anti-tumor cell) to redirect T cells, vaccines to induce tumor-reactive T cells, and adoptive transfer of ex vivo activated, tumor-reactive T cells. In this review, we focus on studies in which high-affinity folate receptors (FRs) on tumor cells have served as targets for redirecting or enhancing the effectiveness of activated T cells. Bispecific antibody conjugates of folate and antibodies to the T cell receptor (TCR) complex can generate tumor-reactive T cell responses. The development of folate/antibody conjugates specific for the T cell co-stimulatory molecule CD28 could yield activated T cells that recognize endogenous peptide-major histocompatibility complex (MHC) antigens on tumor cells. Finally, we discuss a less investigated area in which high-affinity FRs on macrophages, or other antigen presenting cells (APCs), may provide opportunities in the design of tumor-antigen-specific vaccines.     

A novel drug of elotuzumab for treatment of refractory/relapsed multiple myeloma: a meta-analysis of eight trials

Elotuzumab was approved by the US FDA in 2015 as a new drug for the treatment of multiple myeloma (MM), and it became a new choice for MM patients. The drug is the first immunostimulatory drug to treat MM and used to treat recurrent/refractory multiple myeloma (R/RMM) in combination with lenalidomide and dexamethasone. Therefore, we collected the reports from existing clinical trials to analyze the efficacy of the drug in clinical applications to better evaluate the effects of the drug on R/RMM. The search strategy used “elotuzumab” and “multiple myeloma” as keywords to search from the database of Cochrane, Embase, PubMed and Medline. The heterogeneity among the studies was assessed using the Cochrane χ² test, and its extent was evaluated using I² statistics. A P value of less than 0.05 was considered as statistically significant. All meta-analyses were conducted with R Software 3.3.2. We identified eight prospective studies consisting of 608 MM patients. The meta-analysis showed that the overall response rate (ORR) was 63%, 162 patients (26.6%) achieved a very good partial response rate (VGPR), and 34 patients (5.59%) achieved complete response rate (CR). The most common adverse effects of the drug included anemia, lymphopenia, thrombocytopenia, neutropenia and fatigue. Therefore, elotuzumab combination regimens offered clinical benefits to R/RMM patients, and such a combination therapy was a suitable option for continuous treatment for R/RMM patients.     

多发性骨髓瘤靶向新药研究进展

多发性骨髓瘤（MM）是无法治愈的恶性浆细胞肿瘤。尽管随着免疫调节剂（IMiD）、蛋白酶体抑制剂（PI）等靶向新药的广泛应用,MM患者的预后明显改善,但疾病最终仍会复发进而难治。高危及多重耐药的复发难治性多发性骨髓瘤（RRMM）患者治疗仍面临巨大挑战,亟须针对不同靶点的靶向新药治疗。近10余年来,MM领域靶向新药的研发成果令人瞩目。原有靶向药物的新一代药物,包括第2代PI卡非佐米、第3代IMiD泊马度胺等先后进入临床。免疫治疗领域也取得了长足的进步,针对不同靶点的单克隆抗体、双特异性抗体（BsAb）、抗体偶联药物（ADC）及嵌合抗原受体T细胞免疫治疗（CAR-T）效果显著、安全性良好,是MM治疗未来的曙光。随着MM基础研究的深入,针对MM新的不同靶向的药物,如Bcl-2抑制剂、核输出蛋白1（XPO1）抑制剂等先后进入临床试验及临床应用阶段。综述MM领域靶向新药研究进展。     

非霍奇金淋巴瘤药物研究进展

非霍奇金淋巴瘤（NHL）是一组高度异质性的淋巴系统过度增殖的血液肿瘤,随着对该病分子机制认识的深入,针对不同分子机制的新药及新疗法不断涌现,免疫治疗及小分子药物的出现改变了该病的治疗模式,给高危、复发难治患者带来了更多的治疗选择。近年来调动自身抗肿瘤免疫疗法越来越受到重视,包括嵌合抗原受体T细胞疗法(CAR-T)、抗体偶联药(ADC)、双特异性抗体(BsAb),尤其是靶向肿瘤细胞及效应T细胞的双特异T细胞衔接器(BiTE)展示了令人瞩目的应用前景。针对肿瘤免疫微环境的新型免疫治疗及针对信号通路调控的小分子靶向药物成为NHL的治疗新选择。综述目前NHL领域的药物研究进展及临床应用。     

T细胞受体基因工程T细胞治疗的现状与未来

免疫治疗为肿瘤的治疗带来了新的契机和希望,其中免疫检查点抑制剂、治疗性抗体、肿瘤疫苗、免疫调节剂、过继细胞治疗等显著改善了肿瘤患者的预后,部分晚期肿瘤患者获得了长期生存。T细胞受体基因工程T细胞（T cell receptor-engineered T cell,TCR-T）治疗是将识别肿瘤抗原的T细胞受体（T cell receptor,TCR）导入到患者的外周T细胞中,制备能够特异性识别肿瘤抗原的T细胞,然后将这些基因工程T细胞回输患者的治疗方法。该疗法采用天然的TCR信号,具有更高的治疗潜力和更低的毒性或副作用,并且TCR能够识别更多的肿瘤抗原,因此具有广泛的应用前景。目前,多项TCR-T治疗的临床研究正在开展,现有结果表明TCR-T具有较好的治疗效果,但也存在副作用等问题亟需解决。综述TCR-T治疗的临床研究进展、目前面临的挑战以及未来发展的方向。     

New target antigens for cancer immunoprevention

Prevention of cancer through the activation of the immune system has been explored in recent years in preclinical systems thanks to the availability of several new transgenic mouse models that closely mimic the natural history of human tumors. The most thoroughly investigated model of cancer immunoprevention is the mammary carcinoma of HER-2/neu transgenic mouse. In this system it has clearly been shown that the activation of immune defences in healthy individuals can effectively prevent the subsequent onset of highly aggressive mammary carcinomas. A complete prevention was obtained using a combination of three signals (the so called "triplex" vaccine) that included the specific antigen (p185, the product of HER-2/neu) and nonspecific signals like allogeneic histocompatibility antigens and interleukin 12. The analysis of protective immune responses in models of cancer immunoprevention revealed some unexpected features, in particular the central role of antibodies in immunoprevention, at variance with conventional immuno-therapy which is firmly based on cytotoxic T cells. In the HER-2/neu system anti-p185 antibodies, in addition to immunological functions leading to tumor cell lysis, inhibit p185 dimerization and induce its internalization, resulting in the inhibition of mitogenic signaling. Most current tumor antigens appear to be unsuitable targets for cancer immunoprevention. An ideal antigen should have a crucial pathogenetic role in tumor growth to avoid the selection of antigen loss variants. Downregulation of major histocompatibility complex (MHC) expression during tumor progression frequently limits antigen recognition by MHC-restricted T cells. Thus an ideal antigen for cancer immunoprevention should be recognized both by T cells and by antibodies. Antibody binding to cell surface oncogenic determinants, in addition to complement- and cell-mediated tumor cell lysis, can block mitogenic signaling and induce internalization, resulting in tumor growth arrest. A search for new tumor antigens should be conducted among molecules that are directly involved in neoplastic transformation and are recognizable by the immune response also in MHC loss variants. Novel tumor antigens fulfilling both conditions will be crucial for the development of cancer immunoprevention and will provide new targets also for cancer immunotherapy.     

CAR-T细胞治疗产品非临床药效学研究关注点

CAR-T细胞（Chimeric Antigen Receptor T Cells,CAR-T）是一种表达嵌合抗原受体的基因工程T细胞,也称"活的药物",可以增强基因工程T细胞的特异性,能够以MHC （主要组织相容性复合体,Major Histocompatibility Complex,MHC）非依赖性的方式高度靶向肿瘤抗原,是治疗肿瘤的一种新手段。最近,临床上使用CAR-T细胞治疗复发、难治性血液恶性肿瘤和多发性骨髓瘤取得了很好的疗效;同时,采用CAR-T细胞治疗实体瘤的研发也在积极开展。根据所构建的CAR-T细胞不同的适应证和作用原理,构建不同的动物肿瘤模型,研究CAR-T细胞在动物模型的抗肿瘤活性,可以对CAR-T细胞进行概念验证性研究并证明其体内药效学活性,为临床研究提供有力的数据支持。     

Antibody-based identification of cell surface antigens: targets for cancer therapy

The identification of novel cell surface antigens present on tumor cells is crucial for developing new cancer therapies. Intact, viable cancer cells, which display cancer-restricted antigens in their native conformation and cellular context, provide a rich source of novel antigens. Antibody-based technologies are being used to probe the surface of intact cancer cells for cancer-specific antigen targets. In addition to identifying new proteins, these approaches are generating monoclonal antibodies (MAbs) to cancer-specific epitopes and nonprotein targets not amenable to genomics-based approaches. The multiple cell-based approaches developing epitope-specific MAbs to cancer antigens is likely to usher in a new era of therapeutic MAb target discovery.