Alemtuzumab therapy in B-cell lymphoproliferative disorders

Alemtuzumab (Campath-1H, Ilex Pharmaceuticals, San Antonio, TX) is a humanized monoclonal antibody that recognizes the CD52 antigen expressed on malignant and normal B lymphocytes. It has come to be used therapeutically in B-cell malignancies. Responses are seen in non-Hodgkin's lymphoma (NHL), and alemtuzumab can induce molecular remissions in relapsed chronic lymphocytic leukaemia (CLL), even when refractory to purine analogues. Most studies reveal the responses to be superior in the absence of bulky disease. Infusion-related side effects such as rigors, hypotension, and nausea are reduced by using the subcutaneous route of administration. Infectious complications are the most important toxicity seen and are related to the depletion of normal lymphocytes. The clinical efficacy in combination with both fludarabine and rituximab is under investigation.     

Establishment of a human B-cell tumor in athymic mice

Human B-cell tumors have been established in athymic, BALB/c mice using the EBV-positive Burkitt lymphoma cell line Namalwa. One-hundred-one of 104 animals (97%) developed tumors 10-14 days following s.c. injection of a mixture of 20 x 10(6) Namalwa and 5 X 10(6) irradiated human fibrosarcoma (HT-1080) cells. Tumors developed at the site of injection and reached approximately 300 mm2 (product of cross-sectional diameters) after 21 days; no metastases were found. Histological analysis showed that tumors consisted solely of lymphoid cells. Immunofluorescence assays demonstrated that while 85% of the tumor cells retained reactivity with the monoclonal B-cell antibody BA-1, 96% retained reactivity with antibody BA-2 and 43% with BA-3. A similar reactivity profile was observed with cultured Namalwa cells. Tumors were passaged serially 10 times without significant change in BA-1, BA-2, or BA-3 reactivity. Indirect immunofluorescence demonstrated that antibody BA-2 reached tumor cells within 2 h following i.p. injection; antigen modulation was not observed. These results demonstrate the suitability of this B-cell model for testing the in vivo efficacy and stability of anti-B-cell immunoconjugates.     

循环肿瘤DNA在B细胞非霍奇金淋巴瘤中的研究进展

从分子水平监测非霍奇金淋巴瘤(NHL)患者的疾病状态对精准的个体化管理具有重要意义。基于新型二代测序的方法能够以极高的灵敏度从外周血中定量检测循环肿瘤DNA(ctDNA),其可克服活组织检查和成像扫描的弊端,作为NHL的新型生物标志物,为治疗前、治疗期间和治疗后的疾病精准分型、预后评估、疗效判断以及复发监测带来新的机遇,并可能最终改善患者预后。     

Overview of antibody therapy in B-cell non-Hodgkin's lymphoma

The main treatment modalities for lymphoma in the past decade have been radiation therapy and chemotherapy. Recently, molecular engineering provided humanized antibodies with promising clinical activity, and rituximab is the first commercially available antibody. This anti-CD20 monoclonal antibody (MoAb) showed little toxicity and demonstrated excellent clinical activity. Given as a single agent, it induces a high-response rate even in pretreated low-grade non-Hodgkin's lymphoma, the effect being higher if administered for a prolonged period of time. Its action is synergistic with chemotherapy, and combination treatment could improve survival in patients with aggressive lymphomas. Rituximab also demonstrated the ability to clear tumor cells from the circulation, allowing for an in vivo purging effect in the setting of peripheral stem cell collection and transplantation. Still, a number of issues related to its use need to be addressed, such as optimal dose and schedule and the situations in which rituximab should be given as a single agent or in addition to chemotherapy or other drugs, such as other MoAbs or interferons. We also need to understand when rituximab should be used in first-line treatment, with which type of chemotherapy the combination is most cost-effective, and patient population that will benefit most from this antibody treatment.     

CAR T-cell therapy for B-cell lymphoma

Chimeric antigen receptor-modified (CAR) T-cell therapy targeting CD19 has revolutionized the treatment of relapsed or refractory B-cell lymphomas. Based on unprecedented response rates and durability of response in high risk B-cell lymphoma patients, anti-CD19 CAR T-cell therapy was rapidly approved by the FDA for a variety of lymphoma subtypes. Anti-CD19 CAR T-cell therapy is now considered standard of care for patients with relapsed or refractory (R/R) aggressive non-Hodgkin's Lymphoma (NHL) after 2 or more lines of therapy. Three second-generation anti-CD19 CAR T-cell products have been FDA approved for R/R aggressive B-cell lymphoma and FDA approval has been obtained for Mantle Cell Lymphoma and Follicular lymphoma as well. This has ensured broad access to CAR T-cell therapy for patients with NHL and new real-world trials have helped confirm feasibility of CAR T-cell therapy for a broad patient population. The emergence of CAR T-cell therapy will likely provide a new patient population who is status post anti-CD19 CAR T-cell therapy. Investigation of mechanisms of failure of CAR T-cell therapy and clinical trials to study strategies to address this are thus required. Here we provide a thorough review on the use of the FDA approved anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel in patients with indolent or aggressive B-cell lymphoma, and touch on mechanisms of failure of CAR T-cell therapy and potential approaches which are currently under investigation to address this.     

大麻二酚在肿瘤治疗中的应用

大麻二酚(CBD)是植物大麻提取物的主要成分。CBD是非精神活性物质,无成瘾性、毒性低、安全性高。因其具有良好的抗炎、抗氧化、神经保护等作用成为研究热点,已被用于治疗多种难治性癫痫。CBD在肿瘤治疗中展现独特优势,其机制有:(1)诱导细胞周期阻滞,抑制肿瘤细胞增殖;(2)增加肿瘤细胞活性氧家族水平、诱导线粒体功能紊乱、调控Bcl-2家族蛋白、抑制IAP家族蛋白功能等多种途径,促进肿瘤细胞凋亡;(3)抑制肿瘤细胞迁移和侵袭;(4)联合其他抗癌治疗发挥更强的抗肿瘤作用;(5)缓解诸如疼痛、焦虑、抑郁等肿瘤相关症状;(6)可能存在调节肿瘤微环境的作用。CBD在多种肿瘤治疗中展现出良好的抗肿瘤特性,有望作为一种新的肿瘤治疗药物投入临床使用。目前CBD与肿瘤治疗相关的临床试验主要聚焦于对晚期肿瘤患者的镇痛治疗,其直接治疗作用仍有待进一步临床试验。     

Cytokines in tumor therapy

In cases of hairy cell leukemia, chronic myelogenous leukemia, and in benign larynx papilloma, interferon alpha has proved to be a valuable therapeutic principle. Regarding most malignant diseases, however, we are still at the beginning of the therapeutic application of cytokines. New therapeutic strategies include the combination of cytokines together with cytotoxic substances, the combination of in vitro activated T-lymphocytes and natural killer (NK) cells together with cytokines, and, finally, the application of cytokine cocktails. Based on presently performed clinical studies, a slight optimism might be justified with regard to the development of new therapeutic modalities for Hodgkin's disease as well as non-Hodgkin's lymphomas and solid tumors.     

惰性B细胞淋巴瘤的靶向治疗研究进展

惰性B细胞淋巴瘤目前仍是不可治愈的疾病.随着研究的不断深入,其治疗药物和方案层出不穷,靶向药物CD20单抗、布鲁顿酪氨酸激酶(BTK)抑制剂、免疫抑制剂、蛋白酶体抑制剂、免疫检查点抑制剂等在惰性B细胞淋巴瘤中的临床试验结果可能会影响未来的治疗策略.现结合第59届美国血液学会(ASH)年会报道,对惰性B细胞淋巴瘤靶向治疗的重要临床试验新进展进行介绍.     

Bcl-2 antisense therapy in B-cell malignant proliferative disorders

Opinion statement Overexpression of Bcl-2 oncogene has been clinically associated with an aggressive clinical course, chemotherapy and radiotherapy resistance, and poor survival in patients with malignant B-cell disorders. Patients with relapsed or refractory chronic lymphocytic leukemia, multiple myeloma, or non-Hodgkin’s lymphoma have limited therapeutic options. Preclinical and early clinical data have shown that Bcl-2 oncoprotein can be decreased by Bcl-2 antisense therapy. Also, downregulation of Bcl-2 protein can result in reversal of chemotherapy resistance and improved antitumor activity of biologic agents. Various clinical trials are evaluating the role of targeting Bcl-2 as a mechanism to enhance the antitumor potential of chemotherapy and immunotherapy. Early results from these clinical studies are encouraging and confirm the proof of principle for antisense therapy. As current data mature, these trials will hopefully validate preliminary results and establish Bcl-2 antisense as an important addition to the current armamentarium used in the treatment of patients with B-cell neoplasms.v     

Polyamines in brain tumor therapy

Summary In the search for ways to augment current brain tumor therapies many have sought to exploit the fact that adult brain tissue is virtually lacking in cell division. This endorses a special appeal to therapeutic approaches which target the dependence on cell division for brain tumor growth. Polyamines play an essential role in the proliferation of mammalian cells and depletion results in inhibition of growth. As a result, there are investigations into the feasibility of controlling tumor growth by targeting the enzymes in polyamine metabolism with specific enzyme inhibitors. DFMO, an inhibitor of putrescine synthesis, is a cytostatic agent which in combination with tritiated radioemitters or cytotoxic agents such as, MGBG or BCNU is an effective antitumor agent, but the effectiveness of DFMOin vivo is reduced by tumor cell uptake of polyamines released into the circulation by normal cells and from gut flora or dietary sources. However, DFMO therapy combined with elimination of exogenous polyamines inhibits tumor growth but also results in body weight loss, reduced protein synthesis and evidence of toxicity. Furthermore, tumor growth recurs upon termination of treatment. In contrast, competitive polyamine analogs function in the homeostatic regulation of polyamine synthesis but fail to fulfill the requirements for growth and they continue to inhibit tumor growth for several weeks after cessation of treatment. Analogs are now in clinical trials. However, their action may be highly specific and differ from one cell type to another. We suggest that the effectiveness of polyamine based therapy would be enhanced by two approaches: local delivery by intracerebral microdialysis and tumor cell killing by internal radioemitters such as tritiated putrescine or tritriated thymidine which are taken up in increased amounts by polyamine depleted tumor cells. The growth inhibition by polyamine depletion prevents the dilution of the radioactive putrescine and thymidine. The overload of radioactivity kills the growth inhibited cells so that growth cannot recur when treatment terminates.     

溶瘤病毒治疗肿瘤研究进展

溶瘤病毒通过病毒复制导致肿瘤细胞裂解。溶瘤病毒用于肿瘤的治疗已经有近60年的历史,已有大量研究对病毒的改造、给药途径探索、疗效观察、机制及危险性等方面进行了广泛探讨,对溶瘤病毒的认识有了很大进展,溶瘤病毒有望成为治疗肿瘤的重要武器。现综述溶瘤病毒发展、分类及其溶瘤机制,并分析溶瘤病毒在肿瘤治疗中的优缺点和研究现状。     

细胞因子疗法在肿瘤治疗中的应用

细胞因子在肿瘤的发生发展中起着重要作用,部分细胞因子的抗肿瘤机制研究较明确.目前应用于肿瘤临床治疗的细胞因子主要有干扰素(IFN)、白细胞介素(IL)、肿瘤坏死因子(TNF).由于细胞因子疗法作用缺乏靶向性,不良反应多导致部分患者难以耐受,细胞因子疗法临床进展受限.提高疗效稳定性、减少不良反应仍是发展肿瘤细胞因子疗法的重中之重.     

B细胞非霍奇金淋巴瘤靶向药物治疗研究进展

B细胞非霍奇金淋巴瘤(B-cell non-Hodgkin's lymphoma,B-NHLs)代表了一组异质性的来源于血液系统的恶性肿瘤,目前针对B-NHLs一线治疗方案仍是经典标准R-CHOP方案。近几年,靶向阻断分子或细胞机制在淋巴瘤中具有改变临床实践的意义,靶向治疗手段已成为了越来越重要的预测和肿瘤治疗方案,本文就近年来B-NHLs靶向治疗新进展作一综述。     

Lymphoma B-cell responsiveness to CpG-DNA depends on the tumor microenvironment

Background

Toll-like receptor (TLR) agonists have important properties that can be exploited for immunotherapy against tumors. Locally injected immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG-ODNs), which are TLR9 agonists, have shown promise in cancer models. Several studies have demonstrated that these motifs have immunologic effects similar to those of bacterial DNA and can stimulate monocytes, macrophages, dendritic, and B cells, which then produce several proinflammatory cytokines. However, these CpG-ODNs appear to produce opposite effects on tumor B cells.

Methods

In this study, we investigated the direct effects of a murine class B CpG (1826) ODNs on lymphoma B cells in vitro and in vivo, using mouse models of non-Hodgkin B lymphomas developing in immunoprivileged sites, specifically the brain and the eye, and in subcutaneous sites.

Results

In vitro, CpG-ODNs produced antiproliferative and proapoptotic effects on lymphoma B cells. In vivo, it had an antitumor effect when injected into tumors in murine models of subcutaneous lymphoma (SCL) and primary cerebral lymphoma (PCL). However, its intravitreal administration into a primary intraocular lymphoma (PIOL) mouse model did not produce an antitumor effect. In vitro experiments using supernatant from mouse PIOL samples demonstrated that the PIOL molecular microenvironment inhibits the antiproliferative effect of CpG-ODNs on lymphoma B-cells.

Conclusions

Responsiveness to CpG stimulation differs in subcutaneous, cerebral, and ocular tumors, according to the tumoral and molecular microenvironment, and this should be considered for further therapeutic approaches.