SOHO State of the Art Updates and Next Questions: T-Cell–Directed Immune Therapies for Multiple Myeloma: Chimeric Antigen Receptor–Modified T Cells and Bispecific T-Cell–Engaging Agents

Therapeutic monoclonal antibodies targeting SLAMF7 and CD38 are the first classes of targeted immunotherapies approved for multiple myeloma, a cancer of plasma cells. These agents are effective, particularly in combination with the immunomodulatory drugs lenalidomide and pomalidomide. The next generation of myeloma immunotherapy under investigation consists of T-cell–directed strategies designed to promote cytotoxic activity against myeloma cells, as embodied by chimeric antigen receptor–modified T cells (CAR-T) and bispecific T-cell–engaging agents. Early clinical trial results with these classes of therapies are promising, with high response rates reported. These strategies appear to be strong activators of immunoresponse, and adverse effects, particularly cytokine release syndrome and cytokine-related encephalopathic syndrome, are common. Ongoing research explores the optimal disease setting and combination therapies for these agents. These studies provide an unprecedented opportunity to understand the mechanisms of action and their relations to adverse effects and resistance to therapy.     

Immunotherapy to get on point with base editing

Engineered immune cell therapy is revolutionising the field of cancer therapeutics. US Food and Drug Administration (FDA) approval of two chimeric antigen receptor (CAR)-T cell products for the treatment of haematological malignancies paved the way for individualised cancer treatment. However, multiple genetic edits will be required to improve the efficacy of CAR-T cell therapies if they are to treat refractory malignancies successfully, particularly solid tumours. Off-target effects of CRISPR–Cas9-mediated multiplex editing are likely to hinder its safety and application in the clinic. Novel base editing technologies offer a promising and safer alternative for simultaneous editing that could enhance allogeneic engineered immunotherapies for targeting solid tumours and other complex human diseases.     

基于PiggyBac转座系统的CD19-CAR载体的构建及功能鉴定

目的：开发基于PiggyBac(PB)转座系统的电转染CAR-T细胞制备方法并鉴定其体外抗肿瘤功能。方法：采用健康人外周血单个核细胞（PBMC）制备T细胞,通过分子克隆技术将CD19基因克隆到PB质粒（转座子）中后经电转染法将转座子和转座酶质粒导入激活的T细胞中,并测定其转染效率,最后运用流式细胞术及荧光素酶发光实验评估其对人Burkitt’s淋巴瘤Raji细胞的杀伤能力。结果：电转染制备的CD19 CAR-T细胞转染效率较高（>60%）,呈剂量依赖性,且CAR-T细胞相对于Pan-T细胞对Raji细胞杀伤能力显著（P<0.05）。结论：开发的PB转座系统的电转染方法可行,在体外对肿瘤细胞具有显著的杀伤能力,具备临床运用于CD19 CAR-T细胞制备的潜力。     

肿瘤免疫细胞治疗的现状及展望

肿瘤免疫细胞治疗近年来因其疗效显著而备受瞩目.免疫细胞,包括T细胞、NK细胞和DC在抗肿瘤免疫应答以及肿瘤免疫治疗中发挥了重要作用.其中,嵌合抗原受体(chimeric antigen receptor,CAR)修饰T细胞(CAR-T)技术和逆转肿瘤免疫抑制功能的CTLA4和PD-1/PD-L1等免疫检查点抑制剂疗法分别在血液肿瘤及黑素瘤等实体肿瘤治疗中取得了令人振奋的效果,如何进一步提高疗效、增加适应性肿瘤病种并控制其免疫相关的不良反应成为日后研究重点;NK细胞也将利用CAR技术和免疫检查点抑制剂进一步增强其在肿瘤治疗中的作用;DC作为第一个被FDA批准的治疗性肿瘤疫苗,在证明其安全无毒副作用的基础上,如何提高疗效成为关注热点.本文结合近年来肿瘤免疫细胞治疗的进展及该领域中亟需解决的问题作一分析与展望.     

CAR-T细胞免疫治疗肿瘤的毒副反应及临床对策

嵌合抗原受体T细胞(chimeric antigen receptorT cell,CAR-T)是肿瘤免疫治疗的重要手段,具有较强的抗肿瘤活性,但临床毒副反应明显.CAR-T细胞可通过识别共表达靶抗原及交叉抗原的组织等机制,引起肿瘤溶解综合征(tumor lysis syndrome,TLS)和细胞因子释放综合征(cytokine release syndrome,CRS)等全身性损伤.有效监测和及时处理是防治毒副反应的关键,本文结合多个CAR-T细胞治疗肿瘤临床研究的结果与经验,对CAR-T细胞治疗肿瘤的相关毒副反应及临床对策作一阐述.     

Cellular immunotherapy for hematological malignancy: recent progress and future perspectives

Advancements in the field of cellular immunotherapy have accelerated in recent years and have changed the treatment landscape for a variety of hematologic malignancies. Cellular immunotherapy strategies exploit the patient’s immune system to kill cancer cells. The successful use of CD19 chimeric antigen receptor (CAR) T-cells in treating B-cell malignancies is the paradigm of this revolution, and numerous ongoing studies are investigating and extending this approach to other malignancies. However, resistance to CAR-T-cell therapy and non-durable efficacy have prevented CAR-T-cells from becoming the ultimate therapy. Because natural killer (NK) cells play an essential role in antitumor immunity, adoptively transferred allogeneic NK and CAR-modified NK cell therapy has been attempted in certain disease subgroups. Allogenic hematopoietic stem cell transplantation (allo-HSCT) is the oldest form of cellular immunotherapy and the only curative option for hematologic malignancies. Historically, the breadth of application of allo-HSCT has been limited by a lack of identical sibling donors (ISDs). However, great strides have recently been made in the success of haploidentical allografts worldwide, which enable everyone to have a donor. Haploidentical donors can achieve comparable outcomes to those of ISDs and even better outcomes in certain circumstances because of a stronger graft vs. tumor effect. Currently, novel strategies such as CAR-T or NK-based immunotherapy can be applied as a complement to allo-HSCT for curative effects, particularly in refractory cases. Here, we introduce the developments in cellular immunotherapy in hematology.     

Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting 2018

Herein, we summarize the novel clinical data for multiple myeloma (MM) that were presented in the 2019 Annual Meeting of the American Society of Hematology. Triplet regimens including lenalidomide-dexamethasone for high-risk smoldering MM are effective but longer follow-up data are needed. Among transplant-eligible, newly diagnosed MM (NDMM) patients, carfilzomib- and daratumumab-based combinations are promising as effective and safe induction regimens and do not impair stem cell collection. Maintenance with ixazomib results in prolonged progression-free survival (PFS) compared with placebo. Regarding transplant-ineligible NDMM patients, large phase III studies showed that the additional use of daratumumab in backbone first-line regimens provides deep responses and PFS prolongation, whereas dose-/schedule-adjusted lenalidomide-dexamethasone has similar efficacy and is more tolerable than continuous lenalidomide-dexamethasone. In the relapsed/refractory setting carfilzomib- and daratumumab-based regimens remain highly effective and safe treatments, whereas the introduction of venetoclax, isatuximab, atezolizumab, and oprozomib broadens the therapeutic options. Among heavily pretreated MM patients, selinexor and melflufen showed particularly encouraging results. Novel immunotherapeutic approaches including chimeric antigen receptor T cells against B-cell maturation antigen and bispecific antibodies constitute a promising alternative that remains to be evaluated in later-phase studies.