The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's ...lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically.
We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose.
A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.
The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .).
This paper posits that the choices that global economies are faced with for post-pandemic development range between the extremes of growth-fetishism and green recovery. The paper highlights that ...green recovery and the green transition have different connotations in different parts of the world, leading to a huge divergence in their delineations across the Global North and South. The paper further argues that models of degrowth, which emphasize contraction of economic activities for the cause of nature, cannot be applied in large parts of the developing world. The challenge for a developing nation like India is to understand how and where it can position itself in this gamut of developmental paradigms that range between growth-fetishism and green recovery. The paper proposes that Indian green recovery must be based on the Sustainable Development Goals, hinging on two key elements...
Diabetic cardiomyopathy (DCM) is a chronic complication in individuals with diabetes and is characterized by ventricular dilation and hypertrophy, diastolic dysfunction, decreased or preserved ...systolic function and reduced ejection fraction eventually resulting in heart failure. Despite being well characterized, the fundamental mechanisms leading to DCM are still elusive. Recent studies identified the involvement of small non-coding small RNA molecules such as microRNAs (miRs) playing a key role in the etiology of DCM. Therefore, miRs associated with DCM represents a new class of targets for the development of mechanistic therapeutics, which may yield marked benefits compared to other therapeutic approaches. Indeed, few miRs currently under active clinical investigation, with many expressing cautious optimism that miRs based therapies will succeed in the coming years. The major caution in using miRs based therapy is the need to improve the stability and specificity following systemic injection, which can be achieved through chemical and structural modification. In this review, we first discuss the established role of miRs in DCM and the advances in miRs based therapeutic strategies for the prevention/treatment of DCM. We next discuss the currently employed chemical modification of miR oligonucleotides and their utility in therapies specifically focusing on the DCM. Finally, we summarize the commonly used delivery system and approaches for assessment of miRNA modulation and potential off-target effects.
Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, ...treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma.
The outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is poor, particularly in patients ineligible for stem cell transplantation or who fail induction therapy or ...salvage therapy. The phase 1b portion of this open-label, dose-escalation (3+3+3 design) study examined the maximum tolerated dose (MTD) and preliminary safety and activity of the regimen in transplant-ineligible adults with histologically confirmed relapsed/refractory DLBCL after at least 1 prior therapy. Patients received once-daily 560 mg ibrutinib, 375 mg/m2 intravenous rituximab day 1 of cycles 1 to 6, and 10, 15, 20, or 25 mg lenalidomide days 1 to 21 of each 28-day cycle. Forty-five patients were treated; median time since diagnosis was 14.1 months, and 51% of the patients had non–germinal center B-cell–like (non-GCB) DLBCL, 33% had transformed DLBCL, 60% were refractory, and 27% were primary refractory. Because of dose-limiting toxicities, a de-escalation cohort (10 mg lenalidomide) was initiated, and with subsequent re-escalation up to 25 mg lenalidomide, the MTD was not reached. In response-evaluable patients, the overall response rate (ORR) was 44% (complete response CR, 28%); among them, the ORR was 65% (CR, 41%) in non-GCB and 69% and 56% in relapsed (n = 16) and secondary refractory (n = 27) disease, respectively. Overall and for non-GCB, median response duration was 15.9 months, with 2 patients receiving therapy beyond 3 years. Phase 2 was initiated with 20 mg lenalidomide in relapsed/refractory non-GCB, whereas the phase 1b 25-mg lenalidomide cohort was being completed; an additional 25-mg cohort in phase 2 is currently ongoing. This study was registered at www.clinicaltrials.gov as #NCT02077166.
•The safety profile of ibrutinib, lenalidomide, and rituximab in combination was manageable in patients with relapsed/refractory DLBCL.•The combination demonstrated promising and durable activity in relapsed/refractory DLBCL, particularly in patients with non-GCB DLBCL.
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•N-succinylated chitosan (NCS), mangiferin (MGF) are conjugated into a nanohybrid.•The NCS-MGF conjugate particle size is measured as 100 ∼ 200 nm.•FT-IR and COSY analyses revealed ...hydrogen-hydrogen coupling between NCS and MGF.•The blood glucose lowered > 67% on 28 days treatment with NCS-MGF.•The NCS-MGF lowered plasma cholesterol > 37% and serum triglycerides > 61%.
Mangiferin (MGF), from Mangifera indica is well reported for its hypoglycemic activity and hypolipidemic activity. However, MGF suffers therapeutic limitation due to poor solubility causing disparaging bioavailability. Herein to address this problem, we have incorporated MGF in alginate grafted N-succinylated chitosan (NSC) nanomatrix. Characterization by molecular docking, FT-IR and 2D-NMR (COSY) has revealed that MGF could reinforce interaction with NSC. The OH and CH2OH groups of MGF may set interactions with pyranosic OH, CH2OH, NH2 (or NH-succinyl and COOH-succinyl) of NSC. The NSC-MGF nanoconjugate revealed a spherical particle geometry of 100 ∼ 200 nm size. The encapsulated MGF showed 100% release in vitro. In vivo, NSC-MGF nanoconjugate revealed blood glucose lowering from 300 mg/dL to ∼ 90 mg/dL as well as ∼ 37% lowering of total plasma cholesterol. This is well comparative to the earlier reports which acknowledged only 1 ∼ 36% lowering of plasma cholesterol with MGF. Furthermore, NSC-MGF lowered serum trigyceride to ∼ 61%, while in earlier studies, only 10 ∼ 40% serum triglycerides reduction was found with solitary MGF.
Lymphomas may be broadly divided into non-Hodgkin (90%) and Hodgkin (10%) types. Most lymphomas (90%) are of B cell origin but can also be T cell or natural killer cell. Clinical management of ...indolent and aggressive lymphomas is different. Aggressive lymphomas are more dangerous if left untreated yet a higher cell proliferation rate also renders them more chemosensitive, so they are managed with curative intent. Indolent lymphomas are, for the most part, incurable, such that quality of life must be balanced against toxicity of treatment in deciding when and how to treat.
Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors ...(MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry.
We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor-based GVHD prophylaxis.
Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34).
Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD.
Abstract
Oxidative stress has been consistently linked to ageing-related neurodegenerative diseases. Neurodegenerative diseases are characterized by progressive dysfunction and death of neurons. ...Oxidative stress is associated with dysfunction of the mitochondria and endoplasmic reticulum, inducing apoptosis and protein misfolding in neurons. Decreased activities of antioxidant enzymes like SOD, catalase, glutathione, glutathione peroxidase in neurodegenerative states signifies role of reduced antioxidant potential in neurodegeneration. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include Hsp70, heme oxygenase-1, thioredoxin and sirtuins. Cellular signalling pathways and molecular mechanisms that mediate hormetic responses typically involve antioxidant enzymes and transcription factors such as Nrf-2 and NFκB. Vitagenes, either individually or by acting in concert, contribute to counteract the ROS mediated damage. In this review the importance of oxidative stress and the potential use of antioxidants in the prevention and treatment of neurodegenerative disorders are discussed.
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