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Allogenic chimeric antigen receptor T (CAR-T) cells have advantages compared to autologous T cell therapies such as availability cells for production, a suitable HLA-matched donor (if graft-vs-host-disease and rejection effects are to be avoided and also lower risks associated with transduction methods in process of autologous CAR-T cells). In recent years, the additional editing and non-editing technologies are helping to make allogenic CAR-T therapies a hopeful future treatment. Universal off-the-shelf CAR-T cells can be solved key issues include preventing graft-versus-host disease (GVHD) and time consumption and other challenges faced to allogenic CAR-T cells. Here, we have highlighted the improvement in CAR-T development, particularly in engineering allogenic CAR-T, clinical practices related to these, pre-clinical and clinical studies and their successes which investigated in recent 10 years related to treatment of hematological malignancies and cancers by allogenic CAR-T cells.

Cytomegalovirus (CMV) reactivation remains a common and serious complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), often leading to significant morbidity and mortality in immunocompromised recipients. Adoptive transfer of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as a promising immunotherapeutic approach to restore antiviral immunity and prevent CMV-related complications. This interim analysis of a randomized phase I–II clinical trial evaluates the safety and preliminary efficacy of prophylactic infusion of donor-derived CMV-CTLs administered early after allo-HSCT. Twenty adult allo-HSCT recipients were randomized 1:1 to receive either standard care (control group) or a single intravenous infusion of 10 million donor-derived CMV-CTLs per m 2 of body surface area (intervention group) between days + 14 to + 21 post-transplant. The primary endpoint was safety, defined by infusion-related adverse events and incidence of acute graft-versus-host disease (aGvHD). Secondary endpoints included incidence and kinetics of CMV reactivation, measured by serial quantitative RT-PCR during the first 90 days post-transplant. Baseline characteristics were balanced between the two groups. No grade 3–5 adverse events were observed following CMV-CTL infusion. aGvHD grade II occurred in 30% of the intervention group versus 40% in controls. The incidence of CMV reactivation at 90 days was lower in the intervention group (52.00%) compared to controls (77.78%), although not statistically significant (P = 0.580). However, CMV viral loads were significantly lower over time in the intervention group (P = 0.028), suggesting a favorable antiviral effect of CMV-CTLs. Prophylactic infusion of donor-derived CMV-CTLs early after allo-HSCT appears safe and may reduce CMV reactivation and viral burden. These findings support the potential of CMV-CTLs as a novel immunotherapeutic strategy for CMV management in high-risk transplant recipients. Further validation in larger, multicenter trials is warranted.

Hematological malignancies are typically treated with chemotherapy and radiotherapy as the first-line conventional therapies. However, non-coding RNAs (ncRNAs) are a rapidly expanding field of study in cancer biology that influences the growth, differentiation, and proliferation of tumors by targeting immunological checkpoints. This study reviews the results of studies (from 2012 to 2024) that consider the immune checkpoints and ncRNAs in relation to hematological malignancies receiving immunotherapy. This article provides a summary of the latest advancements in immunotherapy for treating hematological malignancies, focusing on the role of immune checkpoints and ncRNAs in the immune response and their capacity for innovative strategies. The paper also discusses the function of immune checkpoints in maintaining immune homeostasis and how their dysregulation can contribute to developing leukemia and lymphoma. Finally, this research concludes with a discussion on the obstacles and future directions in this rapidly evolving field, emphasizing the need for continued research to fully harness the capacity of immune checkpoints and ncRNAs in immunotherapy for hematological malignancies.

Given that natural killer (NK; CD3 − CD56 +) cells-mediated antibody-dependent cell cytotoxicity (ADCC) plays an important role in targeting neuroblastoma (NB) cells, adoptive cell therapy (ACT) utilizing expanded and activated haploidentical NK cells has emerged as a promising immunotherapeutic approach in pediatric patients with high-risk NB. In this pilot study, five pediatric patients with high-risk NB were enrolled. After harvesting hematopoietic progenitor cells (HPCs), patients received an intravenous infusion of high-activity iodine-131 ( 131 I)-meta-iodobenzylguanidine ( 131 I-MIBG). Seven days after the 131 I-MIBG infusion and before the delivery of a single infusion of haploidentical purified NK cells, patients were administered a preparative regimen to establish a lymphodepleted host environment conducive to improved donor NK cell survival. Four days after the NK cell infusion, patients underwent the conditioning regimen, then received autologous hematopoietic stem cell transplantation (AHSCT). All patients achieved successful neutrophil and platelet engraftment. No adverse reactions were noted during or after the infusion of NK cells. Our study shows that incorporating NK cell infusion before AHSCT as a component of the conditioning regimen for consolidative therapy in pediatric patients with high-risk NB can be safe and well tolerated. IRCT Registration Number: IRCT20140818018842N32.

Introduction A new type of immune cell transplantation called allogeneic NK cell infusion is proposed as a potential universal off-the-shelf cell product for adoptive immune cell therapy in hematologic malignancies. Design A multicentral phase I non-randomized clinical trial was conducted to assess the safety, feasibility, and potential efficacy of adoptively infused NK cells in patients with refractory/relapsed AML. We evaluated the feasibility of the trial by considering cell production, patient selection, and treatment protocol. Method Allogeneic NK cells were produced from random healthy unrelated donors; 10 patients were selected according to the inclusion criteria and were included in two groups in case of NK cell dose escalation. Two cell infusions were given, spaced 7 days apart, following a lymphodepletion conditioning regimen of fludarabin-endoxan administered 7 days before the first infusion. The intervention safety was scored using Common Terminology Criteria for Adverse Events (CTCAE) based on variations in vital signs due to cell infusion. NK cell chimerism, tumor burden, and duration of relapse were considered to be components of efficacy. The pilot feasibility evaluation was checked using the CONSORT platform. Results The NK cell infusion procedure was well tolerated, and no grade 2–5 toxicities related (possible or probable) to PB-NK cell infusion were observed. Four patients developed grade 1 transient chills, headaches, vomiting, and bone pain following each PB-NK cell infusion that were not required hospitalization. One of these patients (p01) died because of severe acute respiratory syndrome. Of 9 evaluable patients, 6 (66.6%) showed stable disease (SD) and 3 (33.3%) presented progressive disease (PD). Of 6 SD patients, 2 (p08 and p09) remained alive in SD and 3 patients (p04, p05 and p07) converted to PD at 9 months after infusion of NK cells, and 1 (p03) was not evaluable due to follow-up loss. No patient achieved complete remission. Conclusion The study demonstrated the feasibility and safety of adoptive transfer of random healthy unrelated donor PB-NK cells in refractory/relapsed AML patients and supports continued study in phase II clinical trials in relapsed/refractory AML patients.

Background Relapse is a major cause of treatment failure in high-risk acute myeloid leukemia (AML) after hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cell immunotherapy may enhance graft-versus-leukemia (GvL) effects without increasing graft-versus-host disease (GvHD). This study assessed the safety and feasibility of early post-HSCT prophylactic infusions of third-party NK cells in high-risk AML. Methods In a single-arm, non-randomized trial, 11 high-risk AML patients received two doses of ex vivo expanded third-party NK cells (5 × 10⁶ cells/kg) on days 6 and 12 post-HSCT. Endpoints included safety (CTCAE v5.0), relapse incidence, overall survival (OS), and disease-free survival (DFS). NK cell products were assessed for purity (≥ 80% CD56⁺CD3⁻), cytotoxicity (K562 assay), and expansion. Results NK cell infusion was well tolerated, with no grade 3 or higher infusion-related toxicities. Acute GvHD (Grade 1–2) occurred in 36.4% (4/11); chronic GvHD in 27.3% (3/11). CMV reactivation occurred in 45.5% (5/11) and was managed preemptively. At a median 256-day follow-up (54–514), Relapse occurred in 27.3% (3/11; median: 111 days). Survival was significantly better in patients in CR1/CR2 at HSCT (83.3%) compared to those not in remission (20%; p  = 0.02). Conclusion Early prophylactic NK cell infusions post-HSCT are safe and feasible. Although relapse incidence remains substantial, outcomes appear improved versus historical data. Future randomized trials must confirm clinical benefits and refine timing/dosing strategies.

In recent years, use of exosomes is one of the important approaches to treat cancer. Mesenchymal stem cells are multipotent stem cells which are very putative sources for modulating the immune system and importantly inhibiting immune responses against tumor cells. Small extracellular vesicles (small EVs) are extracted from mesenchymal stem cells can have therapeutic approaches for delivering targeted drugs to cancer cells and also tumors via regulation of signaling pathways. There are challenges in use of exosomes in cancer treatment which need to be improved. Engineering in small EVs can recover the role of exosomes such as drug delivery and therapeutic tools. There are preclinical and clinical studies in the field of mesenchymal stem cells derived from small EVs which demonstrates efficacy of these approaches in the field of cancer. In consideration of problems in large scale production and so on, engineered small EVs as treatment approaches for cancers, it is resulted that they retain most characteristics of cells which are derived from, are responsible for their immunomodulatory impacts driving positive changes in the tumor microenvironment.

Hematological malignancies present significant therapeutic challenges, often complicated by drug resistance, poor bioavailability, and systemic toxicity of conventional treatments. Engineered exosomes have emerged as promising therapeutic carriers, offering unique advantages over synthetic nanoparticles through their natural biocompatibility, enhanced barrier penetration, and intrinsic cell-targeting capabilities. This review examines recent advances in exosome engineering strategies for hematological malignancy treatment, encompassing both parental cell-based modifications and direct engineering approaches. We discuss innovative applications across different malignancies, including targeted delivery of tyrosine kinase inhibitors in chronic myeloid leukemia, small interfering RNA delivery in lymphoma, and proteasome inhibitor transport in multiple myeloma. Notably, engineered exosomes demonstrate remarkable efficacy in overcoming drug resistance mechanisms and enhancing therapeutic outcomes while minimizing adverse effects. Surface modification techniques, including antibody decoration and peptide conjugation, have significantly improved targeting specificity and cellular uptake. Despite promising results, challenges persist in scalable production, standardization, and regulatory compliance. We analyze current limitations and propose future directions, emphasizing the development of standardized protocols, quality metrics, and regulatory frameworks. As this field advances, engineered exosomes show the potential to revolutionize hematological cancer treatment through precise, personalized therapeutic delivery systems with enhanced efficacy and reduced toxicity.

Background Leukemia, a type of blood cell cancer, is categorized by the type of white blood cells affected (lymphocytes or myeloid cells) and disease progression (acute or chronic). In 2020, it ranked 15th among the most diagnosed cancers and 11th in cancer-related deaths globally, with 474,519 new cases and 311,594 deaths (GLOBOCAN2020). Research into leukemia’s development mechanisms may lead to new treatments. Ubiquitin-specific proteases (USPs), a family of deubiquitinating enzymes, play critical roles in various biological processes, with both tumor-suppressive and oncogenic functions, though a comprehensive understanding is still needed. Aim This systematic review aimed to provide a comprehensive review of how Ubiquitin-specific proteases are involved in pathogenesis of different types of leukemia. Methods We systematically searched the MEDLINE (via PubMed), Scopus, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) to identify relevant studies focusing on the role of USPs in leukemia. Data from selected articles were extracted, synthesized, and organized to present a coherent overview of the subject matter. Results The review highlights the crucial roles of USPs in chromosomal aberrations, cell proliferation, differentiation, apoptosis, cell cycle regulation, DNA repair, and drug resistance. USP activity significantly impacts leukemia progression, inhibition, and chemotherapy sensitivity, suggesting personalized diagnostic and therapeutic approaches. Ubiquitin-specific proteases also regulate gene expression, protein stability, complex formation, histone deubiquitination, and protein repositioning in specific leukemia cell types. Conclusion The diagnostic, prognostic, and therapeutic implications associated with ubiquitin-specific proteases (USPs) hold significant promise and the potential to transform leukemia management, ultimately improving patient outcomes.