Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia.
Anti-CD22 免疫毒素 moxetumoab pasudotox 治疗复发或难治性儿童 B 系急性淋巴细胞白血病的国际 2 期研究结果。
- 作者列表："Shah NN","Bhojwani D","August K","Baruchel A","Bertrand Y","Boklan J","Dalla-Pozza L","Dennis R","Hijiya N","Locatelli F","Martin PL","Mechinaud F","Moppett J","Rheingold SR","Schmitt C","Trippett TM","Liang M","Balic K","Li X","Vainshtein I","Yao NS","Pastan I","Wayne AS
BACKGROUND:In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. PROCEDURE:This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. RESULTS:Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. CONCLUSIONS:Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.
背景: 在一项针对儿童复发/难治性急性淋巴细胞白血病 (ALL) 的多中心 1 期研究中，moxetumomab pasudotox，一种 anti-CD22 免疫毒素，显示了可管理的安全性特征和临床活性的初步证据。2 期研究进一步评价疗效。 程序: 这项国际、多中心、 2 期研究招募了接受 moxetumomab pasudotox 40 µ g/kg 每隔一天静脉注射的复发/难治性 B 细胞前体 ALL 儿童, 对于每 21 天周期的六个剂量。主要目的是评价完全缓解率 (CR)。次要目标包括安全性、药代动力学和免疫原性评价。 结果: 32 例患者 (中位年龄，10 岁) 在 16 个地点入组; 30 例接受研究药物，可评价安全性; 28 例可评价反应。客观缓解率为 28.6%，3 例 (10.7%) 达到形态学 CR，5 例 (17.9%) 达到部分缓解。疾病进展 11 例 (39.3%)。10 例患者 (33.3%) 经历了至少一次治疗相关的严重不良事件，包括毛细血管渗漏综合征 (CLS; n = 6)，溶血性尿毒症综合征 (HUS; n = 4), 和治疗相关的肺水肿死亡 (n = 1)。在发生或未发生 CLS 或 HUS 的患者中，未观察到炎症标志物的差异。 结论: 尽管有临床活动的信号，但由于未达到 1 期目标的 CR 率，本 2 期研究在中期分析时终止。临床前数据表明 moxetumoab pasudotox 通过持续输注或联合方案增强疗效; 因此，可能需要进一步研究旨在优化 moxetumoab pasudotox 在儿科 ALL 中的疗效和安全性。
METHODS::Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.
METHODS:The aim of the present study was to explore the possible mechanisms of phosphatase and tensin homolog (PTEN) in the pathogenesis of Burkitt's lymphoma, and provide novel information that can be used in the targeted treatment of this disease. PTEN lentiviral overexpression vector and short‑hairpin PTEN silencing vectors were constructed. The effect of PTEN on the growth and proliferation of CA46 and RAJI cells was analyzed using a Cell Counting Kit‑8 assay. Apoptosis was detected by Hoechst 33342 and propidium iodide double staining. Flow cytometry was used to analyze the cell cycle. A Transwell chamber was used to detect cell migration and invasion abilities. Western blot analysis was used to detect related protein changes. The mechanism of the effect of PTEN on the biological characteristics of Burkitt's lymphoma cells was subsequently analyzed. The results revealed that PTEN inhibited the proliferation of CA46 and RAJI cells by downregulating the expression of p‑AKT, It was indicated that the upregulation of proapoptotic proteins (including Bad and Bax) induced apoptosis, regulated cyclin (including P53, P21, CDK4, CDK6, cyclin D3 and cyclin H) to inhibit cell cycle progression, and mediated epithelial‑mesenchymal transition‑like cell markers (including E‑cadherin, N‑cadherin, β‑catenin, TCF‑8, vimentin, Slug and Snail) to inhibit cell migration and invasion. In conclusion, the tumor‑suppressor gene PTEN inhibited the phosphoinositide 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway and inhibited the proliferation and migration of Burkitt's lymphoma cells, induced apoptosis and cell cycle arrest, thus playing a crucial role in the pathogenesis of Burkitt's lymphoma.
METHODS:Melatonin (Mel) has been shown to involve in many essential cell functions via modulating many signaling pathways. We for the first time investigated that Mel exerted anti-tumor activities in Hodgkin lymphoma (HL) via inhibiting cell proliferation and promoting cell apoptosis. Further study revealed that Mel treatment increased expression of LC3-II and decreased p62 proteins with the enhanced production of autolysosome, indicating it induced activation of autophagy. Nevertheless, Mel treatment together with autophagy inhibitors 3-MA or CQ exacerbated the damage effect of Mel in HL cells, which means autophagy plays a protective role in this process. Furthermore, we found Mel treatment increased the expression of G protein-coupled receptors MT2 and retinoic acid-related orphan receptors (RORs), eg. RORA, RORB and RORC. While RORC has the highest increase in Mel treated HL cells. In addition, RORC overexpression induced autophagy activation. Therefore, Mel showed tumor-suppressive role due to an increased level of RORC induced autophagy in HL.