Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders. However, hematopoietic stem and progenitor cells (HSPCs) from responders exhibit distinct baseline and early treatment-induced CpG methylation changes at regulatory regions linked to tissue patterning, cell migration, and myeloid differentiation. By cycle six-when clinical responses typically emerge-further differential hypomethylation in responder HSPCs suggests marrow adaptation as a driver of improved hematopoiesis. These findings indicate that intrinsic baseline and early drug-induced epigenetic differences in HSPCs may underlie the variable clinical response to AZA in MDS.

Remote ischemic conditioning (RIC) is a simple and low-cost intervention that is thought to increase collateral blood flow through the vasodilatory effects of nitric oxide (NO) produced by the endothelium and red blood cells (RBCs). The aim of this study was to investigate whether RBC form and function are associated with short- and long-term outcomes in patients with acute ischemic stroke, and whether RIC treatment modified this effect.

SARS-CoV-2 infection triggers respiratory inflammation with potentially fatal systemic effects. Mesenchymal stromal/stem cells (MSCs) are promising for treating severe COVID-19 due to their anti-inflammatory and regenerative capacities. This study investigates the effects of allogeneic MSCs in severe COVID-19 pneumonia.

Umbilical cord mesenchymal stem cell-derived (UCMSC-derived) secretome is anti- apoptotic, anti-inflammatory, antifibrotic, angiogenic, and tissue-regenerating. Thus, it may treat systemic lupus erythematosus (SLE). The aim of this study was to investigate the impact of the UCMSC-derived secretome on SLE patients' disease activity, using Mexican systemic lupus erythematosus disease activity index (MEX-SLEDAI) score, complement (C3 and C4) levels, tumor necrosis factor-alpha (TNF-α), anti-double-stranded DNA (anti-dsDNA), and interleukin-6 (IL-6) levels. This double-blind randomized controlled trial investigated the efficacy and safety of UCMSC-derived secretome in SLE patients with moderate disease activity. A total of 29 female patients were randomized into two groups to receive weekly 1.5 cc intramuscular injections of UCMSC-derived secretome or placebo (0.9% NaCl) for six weeks. Disease activity was assessed using the MEX-SLEDAI score, C3 and C4 levels, pro-inflammatory cytokines (IL- 6 and TNF-α), and anti-dsDNA antibodies at baseline, Day 22, and Day 43. Results showed a significant reduction in MEX-SLEDAI scores in the secretome group compared to the placebo group (p < 0.05). Complement C3 levels significantly increased in the secretome group on Day 43, indicating improved immune homeostasis, while C4 levels did not show significant differences between groups. IL-6 and TNF-α levels showed decreasing trends in the secretome group. Anti-dsDNA levels exhibited a decreasing trend in the secretome group, though not statistically significant. Importantly, no severe adverse events were observed, underscoring the safety of the intervention. UCMSC-derived secretome demonstrated immunomodulatory and anti-inflammatory effects, reducing disease activity in SLE patients. These findings suggest its potential as a safe and effective adjunct therapy for SLE, although further studies with larger sample sizes and extended follow-up periods are needed to validate these results.

Neonatal hypoxic ischemic encephalopathy (nHIE) is a serious disease that causes severe and chronic neurological damage. Hypothermia therapy improves patients' outcomes albeit with some limitations, but combining it with treatment with cord blood cells (analogous to mesenchymal stem cells [MSCs]) reportedly improves its effectiveness. TEMCELL HS Inj. (Temcell), a human bone marrow-derived MSC product used for acute graft-versus-host disease, seems an appropriate candidate for this combination therapy. Therefore, we performed a randomized, parallel-group study to compare combined treatment with Temcell and hypothermia versus hypothermia therapy-alone to evaluate the safety and efficacy of Temcell in nHIE patients. The primary endpoint was treatment response defined as an overall developmental quotient of ≥ 85 at 18 months of age. Fourteen patients were enrolled and randomized, with 7 assigned to each group. Both groups had similar demographic characteristics and nHIE severity. Treatment response was observed in 4 of the 6 (66.7%) patients in the Temcell combination group, and in 4 of the 7 patients (57.1%) in the hypothermia therapy-alone group. No marked differences in safety profile were observed between the groups. These results indicate that the efficacy of Temcell combined with hypothermia is comparable to therapeutic hypothermia for patients with nHIE.Clinical Trial Registration: jRCT1080224818.

Mesenchymal stem cell (MSC) has attracted significant attention in clinical research due to their immunomodulatory properties and potential to reduce inflammation in autoimmune disorders, such as multiple sclerosis (MS). This study evaluates the safety and feasibility of placenta-derived MSCs (PLMSCs) in five participants with secondary-progressive multiple sclerosis (SPMS). The primary outcomes focused on safety and tolerability, assessed through adverse event monitoring over six months. Secondary exploratory outcomes included clinical, imaging, and immunological measures. Patients underwent baseline evaluations and follow-up assessments comprising cognitive and psychological assessments, expanded disability status scale (EDSS), clinical signs, diffusion tensor imaging (DTI), functional MRI (fMRI), cytokine levels (IL-10, IL-6, IL-17, TNFα), and CD20/CD19 B cell marker analysis. No serious complications were noted, except for temporary headache in two patients, which was resolved with tablet. Results demonstrated sustained improvements in clinical outcomes, as indicated by significant reductions in EDSS scores (P < 0.0001), cognitive and psychological assessments, and radial diffusivity (RD) indices (P = 0.0186) in DTI metrics over six months. Furthermore, fMRI analysis showed significant enhancements in brain connectivity and cognitive function. Immunologically, CD20/CD19 B cell markers decreased significantly (P = 0.0077), and anti-inflammatory cytokine IL-10 increased alongside reductions in pro-inflammatory TNFα, IL-6, and IL-17 (P < 0.0001) three months post-therapy. These findings suggest PLMSC transplantation is safe and feasible in SPMS patients. While exploratory outcomes indicate potential clinical and immunological benefits, this phase 1 trial was not designed to assess efficacy. Larger, controlled phase II trials are warranted to validate these preliminary observations and investigate PLMSCs' therapeutic potential in MS.

Aim: To determine the effectiveness of a multidisciplinary rehabilitation program (MRP), integrating mesenchymal stem cells (MSCs) therapy, acupuncture, physiotherapy and physical exercises, in improving the functional recovery in patients with combat-related injuries and chronic critical lower limb ischemia (CCLLI).

Over the past decade, immunotherapeutic strategies-mainly targeting the PD-1-PD-L1 immune checkpoint axis-have altered cancer treatment for many solid tumours, but few patients with gastrointestinal forms of cancer have benefited to date. There remains an urgent need to extend immunotherapy efficacy to more patients while addressing resistance to current immune checkpoint inhibitors. The aim of this study was to determine the safety and anti-tumour activity of knockout of CISH, which encodes cytokine-inducible SH2-containing protein, a novel intracellular immune checkpoint target and a founding member of the SOCS family of E3-ligases, using tumour infiltrating lymphocyte (TILs) genetically edited with CRISPR-Cas9 in patients with metastatic gastrointestinal epithelial cancers.

Preliminary phase I clinical trial results revealed that autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) preserved right ventricular cardiac function. To establish the efficacy of intramyocardial injections of an autologous UCB-MNC product at the time of stage II palliation surgery in patients with hypoplastic left heart syndrome (HLHS).

Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSGs], and skin) and the peripheral blood. After belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non-T cells in the oral tissues. Immune cell frequencies in the OM decreased after treatment, whereas CD4 Treg cells increased in both the MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in the OM. Additionally, salivary transforming growth factor β1 (TGF-β1), a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. The ROCKstar study was registered at www.ClinicalTrials.gov as #NCT03640481.

The β2 common integrin subunit CD18 is essential for leukocyte-endothelial adhesion and extravasation to inflamed or infected tissue. Damaging variants in ITGB2, which encodes CD18, cause leukocyte adhesion deficiency type I (LAD-I), an inborn error of immunity that leads to frequent life-threatening infections and a high risk of death among affected children. Allogeneic hematopoietic stem-cell transplantation (HSCT) represents a curative treatment but is limited by donor availability, a high incidence of graft-versus-host disease, and graft failure.

This study investigates the safety and efficacy of three intra-articular (IA) injections of cryopreserved human placenta-derived mesenchymal stem cells (hP-MSCs) for knee osteoarthritis (KOA) over a 1-year follow-up period.

This phase 2 study evaluated the impact of pegfilgrastim, a single-dose, long-acting granulocyte colony-stimulating factor, on the steady-state mobilization of hematopoietic stem cells into peripheral blood in patients with multiple myeloma (MM) or malignant lymphoma (ML). Efficacy and safety, along with CD34-positive cell mobilization outcomes were assessed in patients with MM, who were randomly assigned to pegfilgrastim (n = 30) or daily filgrastim (n = 31), and ML (pegfilgrastim only, n = 13) cohorts. In the MM cohort, CD34-positive cell counts ≥ 2 × 106/kg were achieved in 100% of patients in the pegfilgrastim group and 96.7% in the filgrastim group (difference: 3.3%; 80% confidence interval: -0.9-7.5%), demonstrating the non-inferiority of pegfilgrastim to filgrastim. All patients in the ML cohort achieved ≥ 2 × 106/kg CD34-positive cell counts. The plerixafor administration rates in the MM cohort were 50.0% and 63.3% in the pegfilgrastim and filgrastim groups, respectively, and 91.7% in the ML cohort. There were no major differences in safety measures between the two groups. Although the sample size was small, particularly in the ML cohort, a single dose of pegfilgrastim demonstrated comparable efficacy and safety to daily doses of filgrastim, indicating its potential for clinical use while reducing patient burden.Trial Registration: jRCT2011210029, NCT05007652.

Chimeric Antigen Receptor-T (CAR-T) cell therapy is effective for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) but is not universally available. We developed a novel humanized CD19-directed CAR-T (HCAR19) approved for Phase 1/1b/2 trials. Patients aged 3-25 years were enrolled with r/r B-ALL and ineligible for allogeneic stem cell transplant. Lymphodepletion utilized standard-dose fludarabine and cyclophosphamide. A 3 + 3 design testing 3 dose-ranges was used to determine Phase-2 Dose (P2D): Dose-A, 1 × 106 HCAR19 cells/kg, Dose-B, 3-5 × 106/kg, and Dose-C, 10-15 × 106/kg. Primary endpoint was overall response rate (ORR) at day-30 on bone-marrow flow-cytometry. From May-2021 to September-2023 12 patients [median age-14 (range: 5-24) years] were enrolled with median bone marrow blasts 19.5% at screening. Cytokine release syndrome occurred in 10 (83%) patients, predominantly Grades 1-2, and Grade-2 immune-cell associated neurotoxicity (ICANS) in 1. All patients had Grade-3 cytopenia. ORR was 91.7% (11/12), complete response (CR) in 8 (66.7%) and partial response in 3 (25%). Seven of 8 CRs were at Dose-levels B and C, all of which were sustained till 12 months follow-up. Patients who received dose levels below 3 × 106/kg, or did not achieve CR, had early loss of response or rapid progression. HCAR19 demonstrated safety, manageable toxicity, and durable remissions. and P2D was determined as 5-10 × 106 HCAR19-cells/kg. CLINICAL TRIAL REGISTRATION: The study is registered in the Clinical Trials Registry- India (CTRI/2021/05/033348 and CTRI/2023/03/050689).

Cardiopulmonary bypass (CPB) is associated with activation of pro-inflammatory cells, which infiltrate tissues and cause injury. Here we explored a novel disposable remover to remove inflammatory leukocytes in order to reduce risk of complications after CPB. This is a substudy within a previously registered clinical trial (NCT05400356) that aims to validate a novel disposable remover to remove activated leukocytes generated during CPB.

Patients with refractory dry eye disease (DED) often face the threat of diminished visual quality and have limited responses to existing treatments. Ocular injection of Mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for DED. Topical eye drops are the clinical favorable choice for drug administration in DED. To date, the clinical use of MSC eye drops has not been reported in settings. This clinical trial represents a groundbreaking exploration into the preliminary therapeutic potential and safety of umbilical cord MSC eye drops for patients with refractory DED, including both non-Sjögren's dry eye (NSDE) and Sjögren's syndrome dry eye (SSDE). The study also aimed to investigate the possible underlying mechanisms.

Chimeric antigen receptor (CAR)-modified NK (CAR-NK) cells are candidates for next-generation cancer immunotherapies. Here we generated CD19-specific CAR-NK cells with 4-1BB and CD3ζ signaling endo-domains (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells using baboon envelope pseudotyped lentiviral vectors and demonstrated their antitumor activity in preclinical B cell lymphoma models in female mice. We next conducted a phase 1 dose-escalation trial involving repetitive administration of CAR-NK cells in 8 patients with relapsed/refractory large B cell lymphoma (NCT05472558). Primary end points were safety, maximum tolerated dose, and overall response rate. Secondary end points included duration of response, overall survival, and progression-free survival. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. No cases of cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Results showed an overall response rate of 62.5% at day 30, with 4 patients (50%) achieving complete response. The median progression-free survival was 9.5 months, and the median overall survival was not reached. A post hoc exploratory single-cell RNA sequencing analysis revealed molecular features of CAR-NK cells associated with therapeutic efficacy and efficacy-related immune cell interaction networks. This study met the pre-specified end points. In conclusion, CD19-BBz CAR-NK cells were feasible and therapeutically safe, capable of inducing durable response in patients with B cell lymphoma.

Oroantral communication (OAC) is a significant complication following the removal of maxillary posterior teeth that is a consequence of them being close to the maxillary sinus floor. The current study evaluated the efficacy of four treatment modalities for OAC management: buccal fat pads (BFPs), advanced platelet-rich fibrin (A-PRF), fibrin glue, and oxidized regenerated cellulose plugs. Twenty-four patients with OAC were randomly assigned to four treatment groups (n = 6 each) and clinically assessed for facial swelling, healing outcomes, and patient-reported pain at baseline, on day 3, and at weekly intervals for 4 weeks after their respective treatments. A linear mixed-effects model found a significant reduction in pain over time in all groups. Intergroup and intragroup comparisons of postoperative pain showed statistically significant differences between the groups at baseline and after 1 week. The BFP group had the highest scores for initial pain, while the A-PRF group had the least, with a consistent reduction throughout the study. The BFP group displayed significantly increased facial swelling on day 3, which had subsided after 2 weeks; the fibrin glue group followed a similar pattern but stabilized quickly. The A-PRF group showed minimal swelling and rapid tissue regeneration, while the oxidized regenerated cellulose group displayed less responsiveness for larger OACs. The choice of therapeutic technique for managing OACs should therefore be chosen according to the defect size and anatomical considerations. While BFP and fibrin glue were more efficacious for larger defects, the A-PRF technique showed rapid healing and less discomfort.

A combination of tyrosine kinase inhibitors and chimeric antigen receptor (CAR) T cells has made a breakthrough in refractory or relapsed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, it remains unclear if this treatment in newly diagnosed Ph-positive ALL is associated with high rates of complete molecular remission (CMR) and leukemia-free survival.

Parkinson's disease is a progressive neurodegenerative condition with a considerable health and economic burden1. It is characterized by the loss of midbrain dopaminergic neurons and a diminished response to symptomatic medical or surgical therapy as the disease progresses2. Cell therapy aims to replenish lost dopaminergic neurons and their striatal projections by intrastriatal grafting. Here, we report the results of an open-label phase I clinical trial (NCT04802733) of an investigational cryopreserved, off-the-shelf dopaminergic neuron progenitor cell product (bemdaneprocel) derived from human embryonic stem (hES) cells and grafted bilaterally into the putamen of patients with Parkinson's disease. Twelve patients were enrolled sequentially in two cohorts-a low-dose (0.9 million cells, n = 5) and a high-dose (2.7 million cells, n = 7) cohort-and all of the participants received one year of immunosuppression. The trial achieved its primary objectives of safety and tolerability one year after transplantation, with no adverse events related to the cell product. At 18 months after grafting, putaminal 18Fluoro-DOPA positron emission tomography uptake increased, indicating graft survival. Secondary and exploratory clinical outcomes showed improvement or stability, including improvement in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III OFF scores by an average of 23 points in the high-dose cohort. There were no graft-induced dyskinesias. These data demonstrate safety and support future definitive clinical studies.