Psoriasis vulgaris is the most common form of psoriasis, yet current treatments often lead to significant side effects, resulting in a high rate of therapy desertion. Here, we explored a novel therapeutic approach using the secretome from Wharton Jelly-derived mesenchymal stem cells, biologically stabilized and enhanced with hyaluronic acid (HA), its presentation is an easy-to-apply topical sponge. This formulation had previously demonstrated efficacy in vitro and in experimental psoriasis mouse models.

Natural killer-cell therapies are limited by donor cell sourcing and dose-to-dose variability. FT516 is an induced pluripotent stem cell (iPSC)-derived natural killer-cell therapy expressing high-affinity, non-cleavable CD16 to optimise antibody-dependent cellular cytotoxicity in combination with therapeutic monoclonal antibody. We aimed to assess the safety of FT516 in patients with relapsed or refractory B-cell lymphoma.

Umbilical cord blood-derived cells (UCBCs) are increasingly being evaluated for neuroprotective properties in perinatal brain injury.

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly if treatment is refractory. Mesenchymal stromal cells (MSCs) have demonstrated promising therapeutic effects in aGVHD, due to their well-described immunomodulatory properties. Based on the importance of maternal-fetal interface immune tolerance, the umbilical cord may provide a superior tissue source of MSC. This study aimed to investigate the safety and efficacy of human umbilical cord derived MSCs (hUC-MSCs) delivered as salvage therapy for steroid-refractory (SR)-aGVHD.

Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861.

Givastomig is a bispecific antibody that targets CLDN18.2 and conditionally activates local 4-1BB-expressing T cells. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of givastomig in advanced solid tumors.

Despite being generally safe, apheresis for peripheral blood stem cell collection potentially disrupts electrolyte balance owing to the use of citric acid as an anticoagulant. As prior research has primarily studied hypocalcemia, information on the kinetics of potassium levels during apheresis in healthy donors is scarce. We investigated the fluctuation in potassium levels during apheresis and the risk factors for hypokalemia. This subanalysis used data from an open-label, randomized controlled trial of "oral calcium supplementation versus placebo in mitigating citrate toxicity" conducted between January 2021 and July 2022, at Okayama University Hospital. Potassium levels were significantly reduced after 5-day granulocyte colony-stimulating factor (G-CSF) administration (p < 0.0001), with seven patients (16.7 %) given oral potassium administration before apheresis because the treating physician deemed potassium levels potentially unsafe and three (7.1 %) presenting with hypokalemia at apheresis. Potassium levels after apheresis were significantly lower than those before apheresis (baseline; p < 0.0001), and 28 of 42 donors (66.7 %) experienced biochemical, clinically unapparent hypokalemia immediately after the completion of apheresis. A > 15 % reduction in potassium levels from baseline was associated with age and the acid citrate dextrose solution A (ACD-A) volume in univariate analysis. In the multivariable analysis, both factors were associated (hazard ratio [HR], 11.60; 95 % confidence interval [CI], 1.60-83.70; p = 0.02 and HR, 17.50; 95 % CI, 1.07-136.00; p = 0.04). In conclusion, G-CSF administration and apheresis ultimately induced hypokalemia in two-thirds of the donors. Older age and higher ACD-A volume may affect potassium levels during apheresis in healthy donors. Clinical Trial registration: jRCTs061200035.

The point-of-care, automated manufacturing of chimeric antigen receptor (CAR) T cells can reduce the waiting window and increase the therapy accessibility to patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) as compared with commercially available drug products (DPs). We conducted a phase 1/2 trial (NCT04787263) on the use of second-generation (4.1BB), CD19-CAR T cells, for the treatment of patients with BCP-ALL with either first relapse and very-high-risk (VHR) characteristics or second/subsequent relapse and rapidly progressing disease. CAR T cells were manufactured with a 12-day process using CliniMACS Prodigy, from a fresh apheresis and infused fresh. Three dose levels were tested in the phase 1: 1.0, 2.0, and 3.0×106 CAR+ T cells/kg. Nineteen patients were enrolled, 13 (68%) in first VHR relapse. The designed dose was always successfully produced. No dose-limiting toxicities were observed in the phase 1. Grade 1 to 2 cytokine release syndrome was observed in 13 (68%) patients. Grade 1 to 2 immune effector cell-associated neurotoxicity syndrome occurred in 2 patients and resolved spontaneously. All patients achieved bone marrow complete remission (CR) with negative minimal residual disease. Eight patients (42%) received hematopoietic stem cell transplantation (HSCT) consolidation. Overall, CR was maintained in 13 of 19 patients (68%), 7 of whom having received HSCT. Importantly, all but 1 patient treated with 3.0×106 CAR+ T cells/kg maintained CR. The 3-year event-free survival and overall survival of the whole cohort are 68% and 83%, respectively. Our data suggest that the point-of-care manufacturing of autologous, anti-CD19 CAR T cells can successfully treat patients with BCP-ALL including those with first relapse and VHR characteristics.

&lt;b&gt;Background and Objective:&lt;/b&gt; Diabetic foot ulcers (DFUs) remain a critical clinical problem and stem cell-derived secretome reared under hypoxic conditions has been shown to play a significant role in tissue repair via immunomodulation. This study aimed to evaluate the secretome of human mesenchymal stem cell gel (SH-MSC gel) in DFU patients with grades 2 and 3 through reduced wound volume and modulation of CD163 and NF-κB p50 mRNA expression. &lt;b&gt;Materials and Methods:&lt;/b&gt; A prospective, randomized controlled clinical trial involved 16 DFU patients with grades 2 and 3. Participants received either a placebo gel or an intervention gel containing secretome from Human Umbilical Cord Mesenchymal Stem Cells (hUC-MSCs) cultured under hypoxic conditions. All patients received standard wound care. Primary outcomes included changes in wound volume and expression levels of CD163 and NF-κB p50 mRNA in wound tissue, assessed using quantitative PCR. The Shapiro-Wilk test assessed normality and for normally distributed data, paired t-tests (within-group) and unpaired t-tests (between-group) were used. One-way ANOVA compared means across groups, while the Kruskal-Wallis test followed by &lt;i&gt;post hoc&lt;/i&gt; analysis was employed for non-parametric data (p<0.05). Statistical analysis was performed using GraphPad Prism 10. &lt;b&gt;Results:&lt;/b&gt; Baseline characteristics of participants did not show significant differences between the groups. Treatment with SH-MSC gel significantly enhanced wound healing compared to the placebo group, evidenced by a marked reduction in wound volume after 7 days (95% CI (0.467 to 1.18), p<0.001). The CD163 mRNA expression significantly increased in the SH-MSC gel group post-treatment (95% CI (-2.20 to -1.11), p<0.001), while NF-κB p50 mRNA expression significantly decreased (95% CI (0.349 to 0.688), p<0.001). &lt;b&gt;Conclusion:&lt;/b&gt; The clinical trial results suggested that SH-MSC gel effectively improves wound healing in DFUs. Further research is warranted to explore additional inflammatory markers to better understand DFU treatment.

We conducted a prospective randomized clinical trial to investigate the combination of posttransplant cyclophosphamide (PTCy) and abatacept (Aba) for graft-versus-host disease (GVHD) prophylaxis. Patients with hematologic malignancies undergoing an allogeneic transplant from an 8/8 matched related or unrelated donor were randomized 1:1 to tacrolimus and methotrexate (standard-of-care arm [SOC]) or PTCy on days +3 and +4, followed by Aba on an extended schedule: days +5, +14, and +28, and every 4 weeks up to day +168 (PTCy+Aba). All patients received peripherally collected stem cells. The primary end point was moderate and severe chronic GVHD at 1 year. Following US Food and Drug Administration approval of Aba for GVHD prophylaxis leading to change in institutional SOC, the trial was amended to enroll only on the PTCy+Aba arm. A total of 25 patients enrolled on PTCy+Aba, and 15 on SOC. The trial met its primary end point: Kaplan-Meier estimates of moderate and severe chronic GVHD were 0% on the PTCy+Aba and 65.8% on the SOC arm (P < .0001). GVHD-free, relapse-free survival (GRFS) was 62.5% on PTCy+Aba and 24.1% on SOC (P = .010). There were no treatment-related deaths on PTCy+Aba and 2 on SOC. Overall survival (PTCy+Aba, 92%; SOC, 80%; P = .28), disease-free survival (PCTy+Aba, 68%; SOC, 92.9%; P = .105), and infection rates at 1 year were similar. Grade 3/4 acute GVHD rate was 4.2% on PTCy+Aba and 21.4% on SOC (P = .092). PTCy+Aba preserved regulatory T-cell proliferation and increased CD16+CD56dim cytotoxic natural killer cells. In conclusion, PTCy+Aba is well tolerated and associated with reduced chronic GVHD and improved GRFS. This trial was registered at www.ClinicalTrials.gov as #NCT03680092.

We conducted a phase I trial to determine the safety, tolerability, and preliminary antitumor activity of 131I-metaiodobenzylguanidine (MIBG) combined with the anti-GD2 antibody dinutuximab with or without the histone deacetylase inhibitor vorinostat in patients with relapsed/refractory neuroblastoma (rNBL).

Systemic chronic active Epstein-Barr virus disease (sCAEBV) is a rare intractable EBV-positive T-cell or natural killer (NK)-cell lymphoid neoplasm with systemic inflammation. The only curative treatment is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Disease activity defined by multiple inflammatory symptoms is associated with poor survival. In sCAEBV, signal transducer and activator of transcription 3 (STAT3) is constitutively activated in EBV-infected T and NK cells and promotes their activation and survival. Ruxolitinib, a Janus kinase 1/2 inhibitor, suppresses the STAT3 activation in vitro, suggesting its clinical potential. We conducted a phase 2, multicenter, open-label study to investigate the effects of ruxolitinib on disease activity of sCAEBV. Complete response (CR) and partial response were defined as complete and partial resolution of disease activity, respectively. Nine patients received ruxolitinib, and 7 patients completed the study. The primary end point, CR rate (%) 56 days after the administration or at early termination as defined in the protocol, was 22.2% (2/9). No patient showed hematopoietic toxicity nor disease progression. Notably, 71.4% (5/7) of patients who completed the study were treated at our outpatient clinic. One patient developed a severe adverse event of oral bleeding due to lesion shrinkage during the treatment, and ruxolitinib was discontinued. EBV-DNA levels in whole blood did not change significantly whether the treatment was effective or not. After ruxolitinib treatment, 7 patients received allo-HSCT, and 5 of them achieved CR with undetectable EBV-DNA levels in whole blood. Ruxolitinib is a potent treatment drug that may improve allo-HSCT outcomes by suppressing disease activity of sCAEBV. The trial was registered at University hospital Medical Information Network (UMIN), numbered UMIN000035121.

Zimislecel is an allogeneic stem cell-derived islet-cell therapy. Data on the safety and efficacy of zimislecel in persons with type 1 diabetes are needed.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for advanced hematologic malignancies. HSCT using human leukocyte antigen (HLA)-mismatched donors is historically associated with inferior survival. Patients from underrepresented racial and ethnic groups more frequently rely on HLA-mismatched donors. We hypothesized that post-transplant cyclophosphamide (PTCy) based graft versus host disease (GVHD) prophylaxis would improve outcomes for HSCT recipients using peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors (MMUDs) by reducing the risk of GVHD.

Traumatic spinal cord injury (SCI) is a life-altering condition that results in long-term complications, including progressive neurodegeneration and cord atrophy. It presents a significant unmet medical need with extensive social and economic burdens.

Background: Exosomes (Exos) derived from mesenchymal stem cells (MSCs) share similar biological functions with MSCs but are more stable under various pathophysiological conditions, with a lower risk of immune rejection. Human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising source of MSC-derived exosomes (MSC-Exos), particularly for the treatment of osteoarthritis (OA), a degenerative joint disease characterized by inflammation and cartilage damage.

We aimed to compare individual hypertrophic responses to resistance training in which overload progressed either by adjusting the load (LOADProg) or by increasing the number of repetitions (REPSProg). Furthermore, we investigated whether greater responsiveness to one protocol was associated with chronic changes in myonuclei and satellite cells, proteolysis and extracellular matrix (ECM) remodeling biomarkers.

Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+ T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (TTCR-C4) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, TTCR-C4 cells did not clearly improve outcomes despite EBV-specific TTCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-C4, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting TTCR-C4 persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are recognized as a promising strategy for cell-free therapy, however, their therapeutic role in pulmonary fibrosis remains unrevealed. Here, we report the safety and efficacy of MSC-EVs from human umbilical cord (hUCMSC-EVs) evaluated in mouse models and pulmonary fibrosis patients. We established a rigorous system to produce high-quality of hUCMSC-EVs, characterized by miRNA, protein, and metabolite profiles. When administered via nebulization, hUCMSC-EVs predominantly accumulated in murine lungs and ameliorated bleomycin-induced pulmonary fibrosis, with increased survival rate (from 20% to 80%), restored lung volume, and attenuated injury severity accompanied by elevated oxyhemoglobin saturation and improved pulmonary function evaluations. We performed a phase l clinical trial involving twenty-four patients in a randomized, single-blind, and placebo-controlled study to treat pulmonary fibrosis (MR-46-22-004531, ChiCTR2300075466). All participants tolerated the nebulized hUCMSC-EVs well, with no serious adverse events. Patients receiving the combined therapy of nebulized hUCMSC-EVs and routine treatment demonstrated significant improvements in both lung function indices (forced vital capacity and maximal voluntary ventilation) and respiratory health status (as measured by the Saint George's Respiratory Questionnaire and Leicester Cough Questionnaire. Overall, patients upon the additional therapy with nebulized hUCMSC-EVs gained significant benefits compared with those accepted only routine treatment. Remarkably, two patients with advanced post-inflammatory pulmonary fibrosis exhibited clinically significant regression on serial CT scans after hUCMSC-EVs therapy. These findings suggest that nebulized hUCMSC-EVs could be used as a promising therapeutic strategy for treating pulmonary fibrosis diseases.

Measurable residual disease (MRD) is a major prognostic factor in newly diagnosed multiple myeloma. An assessment of an MRD-guided consolidation strategy in patients who are eligible for autologous stem-cell transplantation (ASCT) may be useful.