BACKGROUND AND AIMS:Cord blood infusion is an emerging treatment for cerebral palsy (CP) currently offered in the United States through clinical trials and an expanded access pathway. This study aimed to understand the barriers and facilitators influencing implementation of cord blood treatment for CP, to help inform future implementation efforts. METHODS:Semi-structured interviews were conducted with US professionals involved in the cord blood treatment program for CP at Duke University and a collaborator site. Data were analyzed using reflexive thematic analysis. RESULTS:From 16 interviews, 5 themes were identified capturing patterned barriers and enablers. Key facilitators included boundary-spanning clinical leadership, interprofessional coordination, dedicated resourcing, responsiveness to community demand, an established safety profile, and a strong research culture. Barriers included the need for cross-disciplinary expertise, uncertainty regarding efficacy evidence, funding and regulatory constraints, and system-level challenges. Participants described that many barriers were overcome to establish the program, while acknowledging that others may persist and are context dependent. CONCLUSIONS:Findings highlight that implementation of cord blood treatment for CP is feasible within specialized settings but contingent on local infrastructure, governance, and workforce capacity. Identified facilitators align with established implementation strategies and offer transferable insights, while underscoring the need for regulatory approval, ethical oversight, and system-level supports to enable equitable and sustainable access to emerging regenerative therapies for CP.

Infantile Krabbe disease (IKD) is a rapidly progressive leukodystrophy for which hematopoietic stem cell transplantation (HCT) offers the only disease-modifying treatment. HCT must occur presymptomatically, ideally by 30 days of life, to optimize survival and neurodevelopmental outcomes. With the expansion of newborn screening for Krabbe disease (KD), pediatric neurologists and geneticists will be responsible for obtaining urgent diagnostic testing and connecting families to experts for information and treatment. Given the variability in state-specific screening protocols, clinicians must be familiar with their local algorithms to act quickly on receiving abnormal results and refer to nearby, specialty treatment centers. Informed consent discussions must clearly outline the natural history of untreated IKD, the requirement for rapid, presymptomatic treatment, and provide a realistic view of the benefits and limitations of HCT. Supportive and palliative care should be prioritized regardless of treatment choice. This publication provides expert guidance on interpreting newborn screening results, conducting rapid confirmatory testing, and referring to and/or establishing treatment centers ready to care for IKD. With anticipatory planning and interdisciplinary collaboration, pediatric specialists can provide accurate diagnosis, compassionate counseling, and expedited evaluation to meet the narrow window for effective HCT.

Introduction Umbilical Cord Blood Transplant (UCBT) is an alternative donor option for patients with non-malignant disorders. However, previous studies have reported variable outcomes, often limited by small sample sizes. Objectives Evaluate overall survival, event free survival, and UCBT outcomes for patients with non-malignant diseases that have undergone a UCBT. Methods and Characteristics We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) on 2429 patients who received UCBT from 1999-2024 for non-malignant conditions: aplastic anemia/autoimmunity (AA; n=208); Inborn errors of immunity (IEI; n=761); hemoglobinopathies (SCD/Thal; n=133); HLH (n=252); other hematological diseases (Heme; n=285); and Inborn errors of metabolism (IEM; n=790). A myeloablative regimen and serotherapy were used in 70% of the patients. The median age at transplant was 1 year (interquartile range (IQR): 0,4) with IEI and IEM being the youngest groups. Most UCBT were allele matched at 5-8/8 loci (73%) with a median total nucleated cell (TNC) dose of 11.8 × 10^7/kg (IQR: 6.8-19.3). Results Overall survival (OS) at 1, 5, and 10 years was 75% (95%CI:73,76), 71% (95%CI: 66,70) and 68% (95%CI: 63,67), respectively, Fig 1. The highest OS was observed in IEI, SCD/Thal, and IEM; (76%), (84%), and (77%), respectively, p<0.001; Fig.2. UCB units infused after 2010 had improved OS compared to earlier transplants: 72% (1152/1607) vs 60% (493/822); p<0.001. The cumulative incidence of neutrophil engraftment by day 42 was 92% with a median of 18 days (IQR: 14-23). Incidence of aGvHD and cGvHD was 45.5% (11.6% severe) and 23.3% (10.7% extensive) respectively. Event-free survival (EFS), defined as survival without graft failure, was 74% (95%CI: 72,76) at 1 year, 66% (95%CI: 64,68) at 5 years, and 57% (95%CI: 55, 60) at 10 years. Graft failure occurred in 17% (n=421) and was significantly associated with decreased survival (p<0.001). Multivariate analysis showed improved EFS in patients <2 y/o (p<0.001), pre-freeze TNC/kg>5 × 10^7(p=0.02), and HLA matching >5-8/8 (p<0.001). EFS were highest in IEI, SCD/Thal, and IEM. Further analysis on pre-freeze TNC/kg showed that HR of EFS is at the lowest when TNC approaches 10-20 × 10^7/kg but increases when exceeding 20 × 10⁷/kg, Fig.3. Intensity of regimen, serotherapy use, ABO, Rh, and recipient CMV status were not associated with improved OS or EFS. Conclusion According to these results, UCBT should be considered among the most effective donor options for patients with non-malignant diseases, especially in younger recipients with higher TNC/kg doses.

Juvenile systemic sclerosis (jSSc) is a rare, chronic, autoimmune disease in children/adolescents and is associated with significant morbidity, skin thickening/hardening (scleroderma), organ toxicity and sub-optimal therapeutic options. In this report, autologous stem cell transplantation is associated with clinical improvement in a 17-year-old with refractory jSSc.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for infants with certain non-malignant inherited disorders and high-risk hematologic malignancies. Infants undergoing HCT differ from older pediatric cohorts as they may present with (i) different indications for HCT (ii) increased sensitivity of developing organs to treatment-related morbidities(iii) rapid clinical deterioration with more subtle early hemodynamic changes and (iv) limited data to predict those who require critical care support (CC). This single center retrospective report included 107 infants who consecutively underwent HCT between 2003 and 2023. Median age at HCT was 5.81 (Q1: 3.45, Q3: 10.55) months, predominantly for non-malignant indications (90.7%) with myeloablative conditioning (87.9%) and unrelated cord blood donors (88.8%). Within 100 days post-HCT, 41% required CC primarily for respiratory distress (77.3%), of which 56.8% (n = 25) required invasive mechanical ventilation (IMV). Infants who required CC had significantly greater risk of mortality as compared to those who didn't (HR: 3.59). Among patients requiring CC, mortality was further associated with longer time to neutrophil engraftment (HR 4.8), need for IMV (HR 10.04), and longer duration of IMV (HR 1.03). Overall survival (OS) among all patients was 85.9% and 73.5% at 100 days and 1-year post-HCT respectively. Among patients who required CC, those who underwent HCT after 2013- had a significantly (59%) lower risk of mortality compared to those transplanted before 2013. While infants undergoing HCT have a disproportionately higher risk of requiring CC, OS is high and continues to improve likely due to advancements in HCT techniques, CC and supportive care.

Background Steroid-refractory acute GVHD (SR-aGVHD) remains a challenging problem that is associated with increased transplant-related mortality. After ruxolitinib failure as second-line treatment for SR-GVHD, patients are at high risk of early mortality with day 100 survivals of 20-30%. 1,2 Remestemcel-L-rknd, an allogeneic mesenchymal stromal cell (MSC) therapy, was FDA approved for SR-aGVHD in pediatric patients based on results of the MSB-GVHD001 trial (NCT02336230).3 Among 54 patients, 78% with grades III/IV disease and treated as second line for SR-aGVHD, day 28 overall response rate(ORR) was 70.4%, with a day 28 survival of 98% (Figure 1) and 70% overall survival (OS) at day 180. Following completion of MSB-GVHD001, Mesoblast provided remestemcel-L-rknd for SR-aGVHD through Emergency Investigational New Drug Applications (EIND). Here we report outcomes of EIND patients treated for SR-aGVHD after failure of second-line or later lines of treatment. Methods This case series includes 53 patients, (<12 years = 28, 12-17 years = 13, ≥ 18 years = 12 patients) with ongoing SR-aGVHD after failing second or later line treatment and with at least 100 days follow-up. Remestemcel-L-rknd, 2 × 106 MSC/kg, was given intravenously twice weekly for 4 weeks, with an additional 4 weekly doses given to patients without a CR at day 28. Results Fifty-five patients were treated at 27 US transplant centers. This included 38 males (72%) and 15 females (28%). Forty-seven (89%) patients had Grade III-IV SR-GVHD and 34 (64%) had received ruxolitinib prior to starting remestemcel-L-rknd. The median number of post-steroid aGVHD medications was 2 (range 1-6). Maximal overall response rate was 60% at day 56. OS through Day 100 was 68% (Figure 1A) with no difference for ages <12, 12-17 or ≥ 18 years, and for prior exposure to ruxolitinib versus no prior exposure. Day 28 OS was 85% with non-relapse mortality of 15 %, including a 14.6 % mortality in patients < 18 years old (n=41). Conclusions Amongst heavily pretreated patients with third line or greater SR-GVHD, 89 % with grades III/IV disease, remestemcel-L-rknd had significant activity with overall day 100 OS of 68%, and similar survival outcomes across both pediatric and adult age groups. This was significantly higher than has been reported with other treatments used in third-line patients and very similar to OS seen with remestemcel-L-rknd in second line children with SR-aGVHD (Figure 1B). Given the high early mortality risk of SR-aGVHD after failure of second line agents, these results highlight that earlier use of remestemcel-L-rknd may increase OS.

Since the identification of hematopoietic stem cells (HSCs) in umbilical cord blood (CB) by Broxmeyer in the 1980s,1 the primary clinical use of CB remains as an unrelated donor source for hematopoietic stem cell transplantation (HSCT). However, the presence of additional progenitor cells and growth factors in CB and cord tissue also makes them readily available sources of cells and biomaterials potentially suitable for use as starting material to manufacture a wide range of evolving biotherapies. CB banks, with their existing infrastructure and readily available inventory of fully characterized CB units, are well-positioned to contribute to the development and implementation of CB and cord-tissue based biotherapies.

CONTEXT:Umbilical cord blood (UCB) is a novel treatment for cerebral palsy (CP), with trials indicating UCB can improve gross motor function. However, heterogeneity has limited the ability to interpret findings. OBJECTIVE:Assess the safety and efficacy of UCB for improving gross motor function in children with CP, including exploring cell dose effect and responder subgroups. DATA SOURCES:Individual participant data from published reports and registered trials identified via systematic searches. STUDY SELECTION:Studies administering UCB to individuals with CP collecting Gross Motor Function Measure (GMFM) scores. DATA EXTRACTION:A 1-stage individual participant data meta-analysis was conducted in R to obtain the pooled effect of UCB and cell dose effect on GMFM using linear mixed models. Responder subgroups were also investigated. RESULTS:Four hundred ninety-eight participant data records were obtained from 11 studies. Main analysis of 170 participants treated with UCB and 171 controls demonstrated UCB increased mean GMFM-66 score compared with controls by 1.36 points at 6 months (95% CI, 0.41-2.32; P = .005) and 1.42 at 12 months (95% CI, 0.31-2.52; P = .012). Mean GMFM-66 effect size increased with increasing cell dose at 3 (P < .001) and 12 months (P = .047). CP severity and baseline age were associated with GMFM-66 effect size. The rate of serious adverse events was similar between groups. LIMITATIONS:Heterogeneity across variables and time points, reducing subanalysis power. CONCLUSIONS:UCB is safe and provides benefit for improving gross motor function in some children with CP, with higher doses associated with increased effect size. Younger participants (aged approximately <5 years) with milder CP showed increased benefit. Findings will help design future trials with precision.

We report the results of 2 independent, concurrently performed studies evaluating the safety and efficacy of donor-derived mesenchymal stromal cell (MSC) infusions in inducing immune-tolerance in nonhuman primate (NHP) and human kidney transplant recipients treated with depletional induction and belatacept/sirolimus maintenance. Fifteen NHPs received rhesus ATG induction and were divided into 3 groups: control (n = 6), pretransplant thymic irradiation (n = 4), and thymic irradiation with monthly donor-MSC infusion (n = 5). Sirolimus was discontinued at day-180, and belatacept at day-365 posttransplant. In humans, 6 patients enrolled in ITN062ST underwent transplantation with alemtuzumab induction; 4 received 12 monthly donor-MSC infusions followed by immunosuppression withdrawal (ISW) if eligible. Donor-MSC infusion was acutely well tolerated in humans and NHPs. Chimerism was not established, and tolerance was not induced in either study. Two of the 5 NHPs that received MSCs rejected while on belatacept monotherapy with detectable donor-specific antibodies. Two patients did not initiate ISW due to de novo donor-specific antibodies and borderline rejection, and 2 patients failed ISW due to reversible rejection. In conclusion, donor MSCs can be given to NHPs or humans repeatedly without acute consequences, but they neither lead to detectable chimerism nor induce tolerance. In a subset of recipients, infused MSCs can be sensitizing.

Background: Hematopoietic cell transplantation (HCT) is the standard of care treatment for children with Hurler syndrome (HS). This study describes the impact of newborn screening (NBS) on HCT outcomes for these patients. Methods: Retrospective study of HS patients diagnosed through NBS and referred to Duke from 2017 to 2023. Patients received a myeloablative busulfan-based regimen and unrelated umbilical cord blood HCT, with cyclosporine and mycophenolate for graft-versus-host-disease prophylaxis. Results: Patients (N =9) were transplanted at a median age of 5.2 months and median weight of 7.8 kg. Median reinfused total nucleated cell was 14.8 x 107/kg. The median times to neutrophil and platelet engraftment were 17 and 48 days, respectively. No primary graft failures or rejections were observed. Post-HCT complications included sinusoidal obstructive syndrome, microangiopathy and autoimmune hemolytic anemia. At median follow-up of 29.1 months (range 4.1-72.2), 8 of 9 patients were alive with normal alpha-L-iduronidase (IDUA) levels, Lansky scores of 90-100%, and developing milestones. One patient died due to autoimmune hemolytic anemia on day +139 (with normal IDUA level and >98% donor chimerism at day +100). Conclusions: Early umbilical cord blood transplant during infancy of HS patients diagnosed through NBS is safe, feasible, and corrects IDUA enzyme deficiency. Follow-up studies will ascertain the long-term benefits of this approach. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:Mesenchymal stromal cells (MSCs) have been employed in clinical trials for their immunomodulatory capabilities, especially in the treatment of autoimmune disorders such as type 1 diabetes. In January (25-26th) 2024, the International Society of Cell and Gene Therapy (ISCT) held a two-day workshop entitled "Cell Therapies for Autoimmune Diseases: MSCs from Biology to Clinical Application" in Paris, France. METHODS:Key opinion leaders in MSC biology, clinical and regulatory backgrounds came together with European, Asian and South American delegates to discuss the need for standardisation in the design, conduct and reporting of MSC clinical trials for autoimmune diseases. RESULTS:The authors of this paper emphasise the need to comply with standard guidelines for protocols and reporting of trials, working towards greater transparency and reproducibility of research. Standardisation in reporting of clinical trials using MSCs for autoimmune disorders is essential so that the reader can interpret data correctly and ensure that meta-analyses are generated from comparable datasets, providing meaningful knowledge and guidelines for those working in the field. CONCLUSION:In this article the key considerations for the effective design and execution of a clinical trial using MSCs for autoimmune disorders, including product characterisation and key manufacturing parameters are discussed. Recommendations are made with respect to minimal criteria for data reporting, so as to move forward the development of MSC therapy and see a successful transition of these drug products to market, thereby addressing a significant unmet clinical need in autoimmunity.

Implantation of cultured allogeneic thymus tissue (CTTI) into athymic human recipients generates functional recipient-derived naïve T cells that are tolerant to the donor. Currently, CTTI is always performed with 12 to 21 days of thymus procurement to avoid culture-related changes that could be detrimental to its reconstitution potential. We demonstrate here that cultured thymus tissue can be cryopreserved and still maintain its viability and reconstitution potential. Implantation of cryopreserved cultured rat thymus tissue (cCTTI) under the renal capsule of congenitally athymic rats results in colonization of the thymus implant with T cell progenitors and population of the periphery with genetically-recipient naïve T cells. Similarly, cCTTI of porcine thymus into the quadriceps muscle of thymectomized T cell-depleted pigs results in full reconstitution of the implanted thymus. Human thymus tissues that are similarly cultured and cryopreserved continue to meet the same implantation quality criteria as freshly cultured thymus tissue. Clinical trials are warranted to test the potential of cCTTI to decouple the current links between time of procurement and implantation. This would extend the benefits of immune reconstitution and tolerance induction to a broader range of patients.

Allogeneic hematopoietic cell transplantation is a potentially curative treatment for malignant and non-malignant hematologic disorders, wherein healthy hematopoietic stem (HSC) and progenitor cells (HSCs) reconstitute a functional blood and immune system following ablation of diseased cells. Functionally potent HSCs/HPCs from bone marrow, mobilized peripheral blood, or umbilical cord blood drive recovery of the hematopoietic system following transplantation. Improving initial characterization of the engraftment potential of donor grafts and recovery time will lead to improved patient outcomes, particularly in the case of umbilical cord blood transplantation, which is limited by low total numbers of cells. However, we still lack a complete understanding of the molecular programs that regulate potency, which is the ability of cells to home to and engraft in a hematopoietic niche, then self-renew and differentiate driving multi-lineage repopulation. Here, we use transcriptomic approaches to elucidate gene programs associated with hematopoietic cell potency in CD34+ cells, which are enriched for HSCs/HPCs. 1) We compared transcriptomic differences between immunophenotypically defined HSCs/HPCs, which have different potentials. 2) We examined the transcriptomic profile of “homing capable” human CD34+ cells from transplantation recipient mouse bone marrow compared to all CD34+ cells used for transplantation. 3) We elucidated the transcriptome of Aldehyde dehydrogenase Bright (AldhBr) CD34+ cells, which are clinical indicators of potent cord blood units, compared to more functionally deficient populations. 4) We used single cell RNA-seq to compare the transcriptome of fresh cord blood HSCs/HPCs with those that are predicted to have lost potency due to cell culture. 5) We analyzed the gene expression profile of potent HSCs from cord blood based on their high long-term engraftment SCID repopulating cell frequencies in an in vivo mouse model compared to those with low engraftment capacity. We validated a novel target using recombinant protein or siRNA mediated knock down in CD34+ expansion assays. Results: Integration of all five data sets identified genes and molecular networks that are highly represented in potent HSCs/HPCs defined by different aspects of potency (homing capacity, cell state, and long-term engraftment capacity). Unsurprisingly, we found that pathways associated with stress, interferon responses, and proliferation were associated with altered potency. We also found a consensus across several or all screens that genes associated with mitochondrial regulation, aldehyde dehydrogenase activity, and hypoxia regulated programs were enriched in potent HSCs/HPCs. By computational integration and manual filtering, we identified a list of genes highly associated with potency that includes PRSS2, AVP, SPP1, MDK, SPINK2, CXCL11, ENO1, BEX2 and PIM1, as well as several mitochondrial genes with expression that negatively correlates with potency such as MT-CO2. Interestingly, many of the potency associated genes code for secreted factors, which may indicate a level of HSC/HPC auto-regulation with regards to potency. We found that treatment with a subset of the identified secreted factors or siRNA-mediated knockdown of genes encoding those proteins potency lead to increased or reduced HPC CFU capacity, respectively, confirming their importance in hematopoietic function ex vivo. We found gene programs associated with hematopoietic cell potency, and validated a subset as important for hematopoietic function ex vivo. The identified gene networks could be used to develop a new potency assay based on gene expression that would simplify donor unit selection for cell therapies. For example, following potency assay validation, cord blood units could be selected for transplantation based on expression levels of PRSS2, BEX2, ENO1, and AVP. Next, we identified molecular programs that can be stabilized to improve cell function for use in therapies, or that could be targetable vulnerabilities in diseased hematopoiesis. These findings could also be important for other cell therapies such as gene editing or CAR-T or CAR-NK therapies derived from HSCs/HPCs, which also require the creation or maintenance of potent cells. In all, these transcriptomic screens are the first step toward elucidating the complex network of molecular programs that contribute to hematopoietic cell function and potency.

IntroductionAllogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for most children with juvenile myelomonocytic leukemia (JMML), but overall survival remains poor at 50%. Given its rarity and heterogeneity, there is no standard HCT conditioning regimen for JMML.MethodsRetrospective study of consecutive patients with JMML who underwent HCT using a busulfan/ melphalan backbone conditioning regimen (n=17) at two academic centers.ResultsThe median age at HCT was 1.9 (range 0.7-6.0) years. At a median follow up of 7.6 (range 2.9-21.5) years, 100% disease-free (DFS) and overall survival (OS), with prompt immune reconstitution were observed. This cyclophosphamide-sparing approach was associated with no transplant related mortality.DiscussionGiven excellent clinical outcomes at extended follow-up, prospective studies are needed to confirm our findings in this ultra-rare disease.

Introduction:Over 300,000 people living in the United States are estimated to have Chagas disease, a condition for which mother to child transmission may occur and early diagnosis is essential to reduce Chagas-related morbidity and mortality. This study evaluated positive Trypanosoma cruzi (T. cruzi) screening serology among maternal donors of umbilical cord blood and assessed the process for linkage to care and treatment for those with Chagas disease. Methods:A retrospective review was conducted of cord blood samples donated to the Carolina Cord Blood Bank in North Carolina from July 2007 to December 2023 with evaluation of positive T. cruzi antibody screening results and outcomes of reflex supplemental testing for Chagas disease. Donors with positive or unknown reflex testing were contacted by phone, and infant testing data were extracted from medical records. Results:Among 27,444 cord blood donations, 52 samples (0.19%; 1.9 per 1000) had positive T. cruzi antibody screening results, with 12 confirmed positive by supplemental testing. All confirmed donors identified as Hispanic/Latinx. Seven donors were started on treatment for Chagas disease, but only four completed it. Cardiac symptoms were later documented in the medical record of three subjects who did not complete treatment. All evaluated infants tested negative for Chagas disease. Conclusions:Screening at-risk pregnant individuals for Chagas disease who have lived in high incidence areas has the benefits of early identification of infection and treatment in people of reproductive age, their children, and extended family members. A protocolized approach to perinatal screening and linkage to care is essential in overcoming barriers to Chagas diagnosis, evaluation, and treatment.

Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes.