Latent Epstein-Barr virus (EBV) infection is asymptomatic in most adults but can be associated with lymphoma, particularly in immunocompromised patients. Options are limited for patients with EBV viremia disease refractory to B-cell depleting antibodies or chemotherapy. Cellular therapies targeting EBV have shown promise in treating EBV-associated malignancies and restoring anti-EBV immunity.

The success of posttransplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has driven efforts to optimize partner therapies that balance GVHD and relapse prevention. We report phase 1 dose-finding results of PTCy, sirolimus (SIR), and VIC-1911, a selective oral Aurora kinase A (AURKA) inhibitor, after myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). Results from murine and in vitro studies informed the development of the novel drug combination. In the phase 1 trial, patients aged 18 to 60 years received myeloablative conditioning, followed by PTCy (50 mg/kg; days +3/+4), SIR (from day +5; target 8-12 ng/mL), and VIC-1911 (25, 50, or 75 mg twice daily; days +5 to +45). The primary end point was achieving <54% phosphorylated histone H3 serine 10 expression in CD4+ T cells by day +21. Preclinical models show that combining SIR with AURKA inhibition suppresses signaling downstream of CD28, enhancing GVHD prevention while leveraging the antileukemia activity of AURKA inhibition. In the phase 1 trial, the optimal VIC-1911 dose achieving target pathway inhibition without dose-limiting toxicities was 75 mg twice daily. Clinical outcomes included no grade 3 to 4 acute GVHD through day 180 (0%) and low rates of moderate/severe chronic GVHD (6%) and relapse (0%) through 1 year (5/16 received maintenance). The 1-year overall survival for this cohort was 94%. VIC-1911 at 75 mg twice daily, combined with PTCy and SIR, effectively suppressed AURKA activity, offering promising GVHD and relapse prevention with a favorable safety profile and promising early clinical outcomes. The trial was registered at www.clinicaltrials.gov as NCT05120570.

This first-in-human, open-label, dose-escalation study (NCT04097652) evaluates UMC119-06, a mesenchymal stem cell product derived from human umbilical cord, for the treatment of acute ischemic stroke (AIS). The study includes two dosing cohorts: 1×10^6 cells/kg and 5×10^6 cells/kg, with three participants enrolled in each cohort. The primary objective is to assess the safety, tolerability, and maximum feasible dose of UMC119-06 in AIS patients, while the secondary objective focuses on evaluating long-term safety and clinical efficacy following a single administration. The study conducted safety assessments across both dosing cohorts, demonstrating that UMC119-06 is well-tolerated, with no adverse events (AEs) classified as possibly, probably, or definitely related to the product. Despite the small sample size of six patients, trends toward positive outcomes were observed in the modified Rankin Scale, the National Institutes of Health Stroke Scale, the Barthel Index, and the infarct volume on brain magnetic resonance imaging. Additionally, changes in biomarkers such as IL-6, TNF-α, VEGF, and HGF suggest a potential impact of UMC119-06 on inflammation, angiogenesis, and tissue repair processes. This Phase I study provides preliminary evidence regarding the safety and potential efficacy of UMC119-06 in AIS patients. Larger-scale studies with control groups are warranted to validate these findings and further explore the therapeutic potential of UMC119-06 for AIS.

Chronic kidney disease (CKD) poses a significant global health burden by reducing quality of life and increasing mortality. Current therapies remain inadequate in halting its progression, necessitating novel treatments to improve outcomes. Adipose-derived stem cells (ADSCs) have emerged as a promising therapeutic option. Phase I/II clinical trials evaluated the efficacy, safety, and tolerability of ELIXCYTE in slowing CKD progression. This multicenter, randomized, open-label study monitored estimated glomerular filtration rate (eGFR) changes over a 48-week period following a single intravenous infusion of ADSCs. Participants were allocated to one of three dosage groups, with primary outcomes assessing eGFR changes and secondary outcomes focusing on safety and tolerability. Results confirmed a favorable safety profile, with no dose-limiting toxicities observed in the low- and moderate-dose groups. Group-based trajectory modeling (GBTM) indicated that, overall, 88.24% of patients exhibited a trend of improvement or stabilization. In the low-dose group, 72.23% of patients demonstrated a stable trend, which was more consistent than in other dosage groups. Furthermore, patients with CKD stage 3B showed a numerically higher proportion of improving trajectories compared to those with stage 4 disease. The low-dose ADSC group exhibited a trend toward more favorable renal function trajectories and fewer adverse events than higher doses, suggesting that lower dosing may provide a balanced profile of safety and potential efficacy. However, despite the preliminary results indicating that ELIXCYTE may effectively slow CKD progression, further large-scale clinical trials are necessary to corroborate these findings and verify the efficacy of ADSC treatment.

Previous studies by the authors have shown that human amniotic membrane extract (AME) potentially improves epithelial damage in corneal and skin lesions. However, questions about its role in diabetic foot ulcer (DFU) treatment remain unanswered. In this study, patients with hard-to-heal DFUs were randomly selected after screening and, after confirming the safety of the AME in an initial selection of patients, the remaining participants were divided into two groups. The treatment group received an AME product (DiAMX, Royan Stem Cell Technology, Iran) (concentration 1mg/ml) with standard of care (SoC), topically, every 48 hours for the first week and then every 72 hours until complete closure. The control group received SoC. Patients were visited weekly, and any improvement, reduction in the wound area and any side-effects were recorded. The results of the safety phase (without the control group) showed that the AME had no adverse events. In the efficacy phase, there was no significant difference in baseline characteristics between the treatment and control groups. The results showed that the wound healing rate was 100% in the treatment group and 77.5±3.12% in the control group (p<0.0001) at week 6. All wounds (n=15) were closed in the treatment group and seven wounds had closed in the control group (p<0.0001). The findings of this study showed that the topical use of DiAMX, in addition to SoC, was patient-friendly, inexpensive, safe and effective in healing hard-to-heal DFUs.

To evaluate the osteogenic potential of dental pulp mesenchymal stem cells in extraction sockets of mandibular third molars by objective assessment of bone density and resorption.

Emerging long-term data indicate relapse rates of >50% after CD19-redirected chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen, we conducted a first-in-human phase 1 clinical trial of zamtocabtagene autoleucel (zamto-cel), a noncryopreserved tandem CD20-CD19-directed CAR T-cell therapy. Two predefined dose levels (dose level 1 [DL1], 1 × 106 and DL2, 2.5 × 106 CAR+ T cells per kg bodyweight) were applied. The primary end point (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events, best overall response (BOR), and biomarker assessments. A total of 12 patients, 6 patients per DL, were treated. No dose-limiting toxicity and no cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome of grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75%, with 5 of 12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with a higher mean maximum observed concentration of zamto-cel and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ central memory T cells in patients with CR, facilitating persistence and improved outcomes in R/R B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal phase 2 clinical trials for patients with R/R aggressive B-NHL. This trial was registered at www.ClinicalTrials.gov as NCT03870945.

Women are born with a limited number of eggs, which decline over time. Premature ovarian insufficiency (POI) occurs when this decline happens before age 40, causing infertility. Bone marrow (BM) stem cells may help restore ovarian function, as some women conceive after BM transplants. Studies suggest that mobilizing stem cells with Granulocyte Colony-Stimulating Factor (G-CSF) can improve ovarian response in women with diminished ovarian reserve, possibly without needing ovarian infusion. Our study aimed to evaluate if G-CSF injections alone could improve ovarian function in women with POI.

Autologous CD133+ bone marrow-derived stem cell (BMDSC) therapy has been designated as an Orphan Drug by the EMA and FDA for the treatment of Asherman Syndrome (AS). This phase 1/2, non-randomized, open-label, single-arm trial assessed the safety and efficacy of this novel therapy in 20 infertile women with moderate to severe AS, unresponsive to prior hysteroscopic treatments. Primary endpoints were safety and tolerability over 15 months follow-up, including during pregnancy and after live birth. The therapy was well tolerated with a mean dosage of 125.41 × 106 cells, with no treatment-related serious adverse events and only reversible events such as arm pain, headache, and nausea. In pregnant patients, minor obstetric complications were reflux-related cough (n = 1), gestational diabetes (n = 2), cervical shortening requiring pessary placement (n = 2), and postpartum placenta accreta (n = 1). No preterm labor occurred, and all six newborns remained free of significant adverse events. Our findings suggest that autologous CD133 + BMDSC therapy is a safe and effective treatment for AS. Clinical trial registration (Eudra CT): 2016-003975-23.

Background and Objectives: MGN-3/Biobran (BRM4, Lentin Plus or Ribraxx) is a natural, rice bran-derived arabinoxylan immunoceutical that modulates the adaptive immune response to viral infections. In response to bacterial infections, basophils act as "first responders" and are also associated with modulation of the adaptive immune response. The maturation of pluripotent CD34+ stem cells into basophils is supported by the cytokine interleukin-3 (IL-3). The aim was to test the hypothesis that modulation of the adaptive immune response in bacterial infection by MGN-3/Biobran entails a basophilic response. The tick-related disorder Lyme borreliosis was chosen as the disease model; tick bites are associated with cutaneous IL-3-mediated basophil recruitment. Materials and Methods: A three-month randomised double-blind placebo-controlled trial was conducted in patients with a history of borreliosis who were suffering from symptoms attributable to this disorder. The immunoceutical group received oral Biobran; the dosage for both groups was 1 g thrice daily. Both groups were matched for age, sex, and ethnicity. Results: A higher percentage of basophil count occurred in the immunoceutical group (p = 0.038). The final general linear model included the group (immunoceutical/placebo) and change in fatigue assessed by the 11-item Chalder Fatigue Questionnaire (CFQ) (r2 = 0.63; p = 0.0066). The change in basophil count was positively correlated with CFQ change (rs = 0.633; p = 0.020); only the immunoceutical group showed a positive correlation. Conclusions: These results support the hypothesis being tested. Basophils may modulate the adaptive immune response by acting as immunoregulatory cells. They can regulate the functioning of type 2 T-helper lymphocytes, enhance immunological memory, and present antigens to CD8 T lymphocytes. Further studies are needed to clarify potential mechanistic factors and the timing of this basophilic response.

Cell therapy has been proposed as a promising treatment for neurological recovery in patients with stroke. However, a strategy to enhance its efficacy is needed, as its clinical benefits have not yet been demonstrated in clinical trials. This study evaluated the efficacy of combination therapy using allogeneic umbilical cord blood (UCB), a relatively safe therapeutic cell source, and recombinant human erythropoietin (rhEPO) in patients with subacute stroke.

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a severe type of epidermolysis bullosa resulting from mutations in COL7A1 gene. Patients experience various degrees of blistering following minor trauma which can over time lead to fibrosis, limb contractures and an increased risk of developing squamous cell carcinoma. The aim was to assess if repeated infusions of allogeneic umbilical cord derived mesenchymal stromal cells (UC-MSCs), CORDStromTM, were safe and could benefit children with RDEB. This was a prospective, double-blinded, randomised, placebo-controlled crossover trial with an internal dose de-escalation trial (for safety) conducted at the two National Paediatric UK EB centres in RDEB children aged >6months and <16years. Participants received IV infusions of 2-3 × 106 cells/kg of UC-MSCs or placebo at day 0 and 14 days later with a 9-month wash out period between the opposite. Main outcomes were change in disease severity as measured by the Epidermolysis Bullosa Disease Activity and Scarring index (EBDASI) and the Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (ISCOREB), wound clinical appearance, pain, itch, and quality of life at 3-months from infusion. Results will be discussed at the meeting. This is the largest study worldwide in children with RDEB. Administering cell therapy early and at regular intervals has the potential to reduce inflammation, effectively modulate disease activity, and lead to clinically meaningful and sustained improvements in disease progression and quality of life. An open-label study is planned and will help us further evaluate the long-term safety and outcomes of CORDStromTM infusions in children with RDEB.

Although research in cell-based therapy is expanding, little is known about patient experience in cell therapy trials to-date. This study explores the experience and attitudes of participants involved in the ASCOT randomized controlled trial, a long-term orthopedic study comparing different cell therapies for the treatment of knee articular cartilage defects.

To prevent graft-versus-host disease (GVHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT), a calcineurin inhibitor plus methotrexate is routinely used. Early phase studies suggested improved outcomes with Orca-T, an allogeneic T-cell immunotherapy that uses purified donor regulatory T cells to prevent GVHD with significantly less immunosuppression. This phase 3 trial randomized adult patients (N = 187) with acute leukemias or myelodysplastic syndrome undergoing myeloablative conditioning to receive either Orca-T with tacrolimus or a conventional allograft with tacrolimus and methotrexate (Tac/MTX), using granulocyte colony-stimulating factor-mobilized peripheral blood from HLA-matched donors. The primary end point was survival free from moderate-to-severe chronic GVHD (cGVHD; cGFS). Using a stratified log-rank test, cGFS was significantly higher in the Orca-T arm than in Tac/MTX (hazard ratio, 0.26; 95% confidence interval, 0.14-0.47; P< .001). One-year estimates were as follows: cGFS was 78.0% with Orca-T vs 38.4% with Tac/MTX; cumulative incidence of moderate-to-severe cGVHD was 12.6% with Orca-T and 44.0% with Tac/MTX (Gray test P< .001); overall survival was 93.9% with Orca-T vs 83.1% with Tac/MTX (P = .12); GVHD-free and relapse-free survival was 63.1% and 30.9% in the Orca-T and Tac/MTX arms (P< .001), respectively; nonrelapse mortality (NRM) was 3.4% with Orca-T vs 13.2% with Tac/MTX (P = .03). Orca-T met the primary end point of improved survival free from cGVHD compared with Tac/MTX prophylaxis and should be considered a new therapeutic option with low toxicity for GVHD prophylaxis. Moreover, significantly less toxicity was observed with Orca-T patients, including fewer serious infectious complications and less NRM. This trial was registered at www.clinicaltrials.gov as NCT05316701.

Traumatic brain injury (TBI) is a significant public health issue, leading to long-term neurological impairments. Current treatments offer limited recovery, particularly in restoring lost functions. Mesenchymal stem cell-derived exosomes (MSCdE) have shown potential for promoting neuroprotection and regeneration. This study evaluates the safety and efficacy of MSCdE therapy in TBI patients.

There is controversy about the benefits of bone marrow mononuclear cells (BMMC) to improve left ventricular dysfunction (LVD) in patients with coronary artery disease. We sought to evaluate the safety, feasibility and efficacy of the intracoronary infusion of BMMC to improve left ventricular ejection fraction (LVEF) in patients with chronic total coronary artery occlusions (CTO).

Steroid-refractory (SR) and high-risk (HR) acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. Mesenchymal stromal cells (MSCs) possess immunomodulatory potential, and Wharton's jelly MSCs, a rapidly expanding subset of cells that exhibit potent in vitro suppression of T-cell proliferation, may benefit patients in the setting of SR/HR aGVHD. The objective of this study was to evaluate the safety and preliminary efficacy signals of multiple-dose MSCTC-0010, an umbilical cord-derived Wharton's jelly MSC product, in patients with SR or HR aGVHD.

Concurrent training is commonly associated with blunted muscle hypertrophy compared with resistance training alone, but the underlying physiological mechanisms remain unclear. This study aimed to investigate the acute and chronic effects of concurrent versus resistance training on muscle protein synthesis, satellite cell dynamics, myonuclear content, myogenic regulatory factor expression, muscle fiber hypertrophy, strength, and aerobic capacity. Nineteen previously untrained young men were randomly assigned to either concurrent or resistance training for 16 wk. Muscle biopsies were collected before and 48 h after a standardized exercise session at weeks 4 and 16. Samples were analyzed for myofibrillar protein synthesis via deuterium oxide incorporation, satellite cell content, myonuclear number, and gene expression. Strength, aerobic capacity, and muscle fiber cross-sectional area were measured at baseline and postintervention. Muscle protein synthesis increased 48 h postexercise at both weeks 4 and 16 (P = 0.0105), with no group differences. Satellite cell content increased over time in type II fibers only (P = 0.0021). Myonuclear number increased in both fiber types (type I: P = 0.0301 and type II: P = 0.0009), with higher values in type I fibers in the concurrent training group (P = 0.0027). MYF5 and MYF6 expression increased over time (P = 0.0141 and P = 0.034, respectively), and MYOD1 was elevated postexercise only in concurrent training (P = 0.0009). Type II fiber size increased (P = 0.016). Strength gains were greater in resistance training (P = 0.016), whereas aerobic capacity improved only in concurrent training (P < 0.001). Sixteen weeks of concurrent training did not inhibit molecular mechanisms associated with muscle hypertrophy in previously untrained individuals.NEW & NOTEWORTHY Sixteen weeks of concurrent training with long-interval HIIT preserved key molecular adaptations related to muscle hypertrophy, including protein synthesis, satellite cell activity, and gene expression. Both concurrent and resistance training increased type II fiber cross-sectional area, but only concurrent training improved V̇o2peak. Although strength gains were lower with concurrent training, molecular and cellular remodeling remained intact, supporting it as an effective strategy to enhance both muscle growth and aerobic fitness simultaneously.

Alzheimer's disease (AD) is characterized by cognitive decline, memory loss, and a gradual loss of daily functioning. Unfortunately, despite extensive research, effective treatments for AD remain limited. Of these, stem cell-based therapies show promise for their regenerative potential and ability to modulate pathological processes. Autologous blood-derived stem cells (ABSCs), which are isolated from a patient's own blood, have demonstrated therapeutic efficacy in AD. This clinical study evaluated the safety and efficacy of ABSCs on patients with AD and investigated the changing levels of growth factors derived from ABSCs treatment. The efficacy of the treatment on cognitive function was assessed using the Mini-Mental State Examination, Clinical Dementia Rating, and AD Assessment Scale-Cognitive Subscale, all widely used tools to assess cognitive function in patients with AD. The neuroimaging and molecular mechanisms were the secondary outcomes. The neuroimaging examinations performed included PET-CT with amyloid imaging, for assessing amyloid plaque deposition in the brain at baseline and at 3 and 6 months after treatment; FDG-PET, for measuring brain glucose metabolism and acquiring insights into neuronal activity and overall brain function; and MRI, performed at baseline and follow-up, for assessing structural brain changes. ABSCs treatment resulted in notable improvements in cognitive function, reductions in amyloid plaque burden, and improved neuroimaging outcomes. Autologous stem cell therapy also reduced the risk of immune rejection, offering a safety advantage over allogeneic stem cell therapies. Furthermore, the use of growth factors to enhance stem cell efficacy aligns with existing research demonstrating improvements in stem cell limitations. This study provides compelling evidence that ABSCs combined with growth factors exhibit significant therapeutic potential for patients with moderate to severe AD. Our findings indicate that our current combination treatment may offer a multi-target approach to addressing the complex pathogenesis of neurodegenerative diseases and is thereby a potentially sustainable therapeutic strategy for AD. Furthermore, the combination of ABSCs with growth factors can potentially provide a much-needed therapeutic alternative for AD.

CD7 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory T-cell acute lymphoblastic leukemia (ALL). Supportive results of first-in-human studies of base-edited anti-CD7 CAR (BE-CAR7) T cells with triple C→T deamination-mediated knockouts of TCRαβ, CD52, and CD7 have been reported previously.