Use Of Umbilical Cord Blood Research Articles

Hematopoietic Cell Transplantation: Practice Predictions for the Year 2023

Research priorities are best determined by the most pressing scientific questions, in the context of current knowledge. However, definitive research studies take time, while real-world experience accumulates. Adoption of new practices before adequate comparison with current treatments threatens successful study conduct and may expose patients to what ultimately turns out to be inferior treatment. We conducted a survey to understand the hematopoietic cell transplantation (HCT) community's predictions about future practice trends in the HCT field and results of ongoing Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials to gauge how the HCT community views the treatments being studied. The survey was distributed between February and March 2019 to an electronic mailing list of HCT clinicians practicing in the United States maintained by the Center for International Blood and Marrow Transplant Research (CIBMTR). Of 986 clinicians surveyed, 315 responded (32%). They predicted an increase in the number of HCTs performed for malignant hematologic diseases and benign diseases such as sickle cell, autoimmune, and genetic disorders. The majority (63%) predicted that matched related donors will remain the preferred donor source for adult HCT recipients in 2023, but 21% predicted haploidentical (haplo) donors and 17% predicted matched unrelated donors would be the preferred source. Most respondents (65%) predicted a decrease in the use of umbilical cord blood (UCB) as a graft source for HCT. Most respondents also predicted that calcineurin-based graft-versus-host disease (GVHD) prophylaxis would be replaced by post-transplantation cyclophosphamide (PTCy) (55%), biomarker use would become standard practice to guide GVHD therapy (73%), and steroids would be combined with other agents as first-line therapy for newly diagnosed acute (53%) and chronic GVHD (54%). In ongoing BMT CTN trials in which outcomes are not yet known, 60% to 92% of respondents had an opinion about which arm they thought would be superior. However, not all respondents predicted the same outcome, with 44% to 88% choosing the same arm. There was no clear relationship between the proportion predicting the same arm would win and accrual to the trial. Survey respondents were optimistic about an increasing volume of transplantation procedures, and they also expected significant changes in HCT practice over the next few years, including wider adoption of PTCy GVHD prophylaxis, increased use of biomarkers to guide GVHD therapy, and decreased use of UCB HCT. The degree of equipoise in the community about the relative efficacy of therapies being studied did not seem to affect accrual to current BMT CTN trials, but this is an area that needs further investigation.

Analysis of the legal regulation of the use of umbilical cord blood and its components in the Russian Federation and abroad

Umbilical cord blood is a unique source of hematopoietic cells for transplantation in hematological diseases and other socially significant pathologies. The development of regenerative medicine requires clear protocols governing the use of umbilical cord blood and its components (cells, plasma) in clinical practice. In the Russian Federation, today, there is no proper regulatory framework for working with umbilical cord blood and its components, which is a limiting factor in the development of cellular technologies and regenerative medicine in general. The article analyzes the legal framework for regulating the use of umbilical cord blood and its components in the Russian Federation and abroad - the countries of the European Union and America.

Umbilical cord blood transplantation: a maturing technology.

The use of umbilical cord blood (CB) as a source of hematopoietic progenitor cells for patients with high-risk hematologic disorders receiving allogeneic hematopoietic cell transplantations (HCTs) has increased significantly. Single-institution and registry studies have shown a decreased relapse rate and an increased transplantation-related mortality rate with similar overall survival rates after allogeneic HCT with CB compared with other donor sources. The transplantation of double CB units has overcome the dose limitation inherent in a single CB unit and thus has markedly extended the use of CB to larger children and adults. Similarly, the use of reduced intensity conditioning in the CB transplantation setting has allowed the treatment of older patients who would be unable to tolerate the myeloablative regimens used in the original CB transplantation protocols.

Single-Cell Mapping of Progressive Fetal-to-Adult Transition in Human Naïve T Cells

Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological “layer” of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid, myeloid, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity — with a substantial degree of interindividual variation at the time of birth — rather than via a transition between discrete waves. These findings have important implications in the design of strategies for prophylaxis against infection in the newborn, and for the use of umbilical cord blood (UCB) in the setting of transplantation.

Single-Cell Mapping of Progressive Fetal-to-Adult Transition in Human Hematopoiesis

Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological “layer” of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid, myeloid, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity — with a substantial degree of interindividual variation at the time of birth — rather than via a transition between discrete waves. These findings have important implications in the design of strategies for prophylaxis against infection in the newborn, and for the use of umbilical cord blood (UCB) in the setting of transplantation.

Contamination Rates by Delivery Method of Human Umbilical Cord Blood Samples in the United Arab Emirates and Gulf Cooperation Council Countries

The use of umbilical cord blood, which is recognized as a rich source of hematopoietic stem cells, has become an alternative source to bone marrow for transplantation. Cord blood units used for transplant might be rejected due to positive bacterial microbiology. According to common cell therapy standards a microbiology bacterial identification is required to know the type of bacterial, and to determine if the bacteria is considered critical or non-critical prior to the transplant determination.

Knowledge and sources of information on umbilical cord blood donation in pregnant women.

The use of umbilical cord blood (UCB) holds promise for the treatment of a wide spectrum of diseases. However, information on UCB donation is not widespread or accurate among expectant women. The aim of this study is to evaluate pregnant women's knowledge of UCB donation, their main sources of information and their satisfaction with the knowledge possessed. Women (N = 375) in the last semester of pregnancy completed questionnaires evaluating sociodemographics, knowledge of UCB donation, past donation, sources of information, satisfaction with the information and the desire to have received more information. Women were aware of the possibility of donating UCB (97.5%) although, on average, they reported not having enough knowledge of donation possibilities, procedures to be followed and uses of UCB (2.51, on a 5-point scale). Considering knowledge satisfaction, 28% were not at all satisfied. Only 2.8% felt fully prepared and the great majority (75.2%) would have liked to have received more information. The main source of information was the Internet (51.2%). Gynecologists and midwives were indicated by only 24.4% and 18.6% of women, respectively. Age and education were significantly correlated with UCB knowledge. Chi-square tests evidenced that those who reported professional sources of information (gynecologists, obstetricians, prenatal courses) did not need additional information. Conversely, mothers who turned to other mothers for information were more likely to desire further information. Most mothers report the Internet as the main source of information. Providing accurate information through official sources may result in a more positive attitude toward donation.

Umbilical cord blood stem cell therapy in premature brain injury: Opportunities and challenges.

Preterm birth and associated brain injury are the primary cause of cerebral palsy and developmental disabilities and are among the most serious global health issues that modern society faces. Current therapy for infants suffering from premature brain injury is still mainly supportive, and there are no effective treatments. Thus there is a pressing need for comparative and translational studies on how to reduce brain injury and to increase regeneration and brain repair in preterm infants. There is strong supporting evidence for the use of umbilical cord blood (UCB)-derived stem cell therapy for treating preterm brain injury and neurological sequelae. UCB-derived stem cell therapy is effective in many animal models and has been shown to be feasible in clinical trials. Most of these therapies are still experimental, however. In this review, we focus on recent advances on the efficacy of UCB-derived stem cell therapy in preterm infants with brain injury, and discuss the potential mechanisms behind their therapeutic effects as well as application strategies for future preclinical and clinical trials.

Distinct Mechanisms Underlying the Ex Vivo Expansion of Human Cord Blood Stem Cells with Different Strategies Currently Used for Allogeneic Transplantation

Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells (HSCs) for patients that require allogeneic stem cell transplantation. The use of UCB in adults is restricted due to the limited number of HSCs within a single unit. This limitation can be overcome by ex-vivo expansion. Several strategies have successfully expanded the numbers of clinically functional HSCs. Such strategies, including the aryl hydrocarbon receptor antagonist, SR1, pyrimidoindole derivative, UM171, nicotinamide, NAM and more recently, valproic acid (VPA), have entered clinical development. HSC grafts expanded by SR1 and UM171 have been reported to establish rapid and sustained hematological reconstitution in allogeneic transplant recipients [1-3]. Our group has started a clinical trial using VPA-expanded allogeneic UCB grafts (NCT03885947). Initial data have shown multi-lineage donor cell reconstitution with especially rapid T cell and platelet engraftment in patients with treatment refractory acute leukemias. To gain insight into the mechanisms underlying these clinical HSC expansion procedures, we recreated the different approaches to compare the various expanded grafts. Although there is successful clinical data with the NAM approach, we were unable to recreate these conditions in our laboratory and therefore, we could not compare these grafts to those expanded with SR1, UM171 and VPA [4-7]. These comparative studies indicated that each strategy increased to varying degrees both the percentage and absolute numbers of CD34+CD133+CD90+EPCR+ as opposed to cultures treated with their respective cytokine cocktail alone. Although SR1 treatment resulted in the generation of greater numbers of total nucleated cells from purified 1x106 UCB-CD34+ cells (16x107 in SR1 vs 8x107 in UM171 and 7x107 in VPA), the numbers of CD34+CD133+CD90+EPCR+ cells (4x105 in SR1 vs, 7x105 in UM171 and 8.7x105 in VPA) as well as of other CD34+ subpopulations with different degrees of stem cell activity were lower than those observed in VPA and UM171-expanded cultures. In order to understand the underlying mechanism by which these agents act, we isolated CD34+CD90-EPCR- cells and treated with VPA, SR1 or UM171. VPA treatment for 24 hrs resulted in acquisition of CD90 and EPCR expression (80% and 25% of cells acquired CD90 and EPCR, respectively). UM171 treatment led to a modest increase in cells expressing EPCR and CD90. By contrast, SR1 treatment did not induce a phenotypic switch. Comparison of RNA-seq data indicated a strong induction of CD90, EPCR and CD133 in the CD34+ grafts expanded with VPA and UM171, but not in grafts generated with SR1. Twenty five out of 53 and 5 out of 9 genes upregulated more than 2 fold by UM171 and SR1, respectively, were also upregulated in VPA-expanded grafts. Eight out of 39 and 6 out of 77 genes downregulated more than 1.5 fold by UM171 and SR1, respectively, were also downregulated in VPA-expanded grafts. However, grafts expanded with each of these agents shared only three upregulated and three downregulated genes suggesting that different mechanisms underlie the actions of each of these agents. In fact, enhanced histone acetylation induced by VPA was not observed in SR1 and UM171 expanded cells. Both UM171 and VPA did not signal through the AHR pathway, which is required for SR1-mediated expansion. These data suggest that these agents target distinct pathways leading to ex vivo HSC expansion. Since mitochondrial activity is an additional critical regulator of the HSC fate, we examined the mitochondrial profile. VPA-expanded HSCs exhibited a remodeled mitochondrial network associated with low levels of mitochondrial ROS and mass. HSCs expanded with UM171 unlike SR1 displayed low ROS levels. Neither UM171 nor SR1 impacted mitochondrial mass. In vivo transplantation of UM171 and VPA expanded grafts in NSG mice showed similar degrees of human cell chimerism (~25%). Whereas both expanded grafts were capable of establishing multilineage hematopoiesis, we found a greater degree of CD34+ and T cell chimerism in NSG mice engrafted with VPA-expanded grafts. Studies of the engraftment potential of SR1 expanded grafts are ongoing. In conclusion, our findings suggest that although VPA, UM171 and SR1 expand greater numbers of human HSCs that are useful for allogeneic stem cell transplantation, their underlying mechanisms of action and pathways involved are different. Disclosures Schaniel: Summer Road: Research Funding. Hoffman:Merus: Research Funding.

Autologous cord blood in children with cerebral palsy: a review.

The aim of this narrative review is to report on the current knowledge regarding the clinical use of umbilical cord blood (CB) based on articles from PubMed and clinical trials registered on ClinicalTrials.gov. An increasing amount of evidence suggests that CB may be used for both early diagnostics and treatment of cerebral palsy. The acidity of CB and its biochemical parameters, including dozens of cytokines, growth factors, and other metabolites (such as amino acids, acylcarnitines, phosphatidylcholines, succinate, glycerol, 3-hydroxybutyrate, and O-phosphocholine) are predictors of future neurodevelopment. In addition, several clinical studies confirmed the safety and efficacy of CB administration in both autologous and allogeneic models, including a meta-analysis of five clinical trials involving a total of 328 participants. Currently, nine clinical trials assessing the use of autologous umbilical CB in children diagnosed with hypoxic-ischemic encephalopathy or cerebral palsy are in progress. The total population assessed in these trials exceeds 2500 patients.

The influence of stem cell source on transplant outcomes for pediatric patients with acute myeloid leukemia

AbstractWhen hematopoietic stem cell transplant (HSCT) is necessary for children with acute myeloid leukemia (AML), there remains debate about the best stem cell source. Post-HSCT relapse is a common cause of mortality, and complications such as chronic graft versus host disease (cGVHD) are debilitating and life-threatening. To compare post-HSCT outcomes of different donor sources, we retrospectively analyzed consecutive transplants performed in several international centers from 2005 to 2015. A total of 317 patients were studied: 19% matched sibling donor (MSD), 23% matched unrelated donor (MUD), 39% umbilical cord blood (UCB), and 19% double UCB (dUCB) recipients. The median age at transplant was 10 years (range, 0.42-21 years), and median follow-up was 4.74 years (range, 4.02-5.39 years). Comparisons were made while controlling for patient, transplant, and disease characteristics. There were no differences in relapse, leukemia-free survival, or nonrelapse mortality. dUCB recipients had inferior survival compared with matched sibling recipients, but all other comparisons showed similar overall survival. Despite the majority of UCB transplants being HLA mismatched, the rates of cGVHD were low, especially compared with the well-matched MUD recipients (hazard ratio, 0.3; 95% confidence interval, 0.14-0.67; P = .02). The composite measure of cGVHD and leukemia-free survival (cGVHD-LFS), which represents both the quality of life and risk for mortality, was significantly better in the UCB compared with the MUD recipients (HR, 0.56; 95% confidence interval, 0.34-1; P = .03). In summary, the use of UCB is an excellent donor choice for pediatric patients with AML when a matched sibling cannot be identified.

ACOG Committee Opinion No. 771: Umbilical Cord Blood Banking.

Since the first successful umbilical cord blood transplant in 1988, it has been estimated that more than 35,000 transplants have been performed in children and adults for the correction of inborn errors of metabolism, hematopoietic malignancies, and genetic disorders of the blood and immune system. Two types of banks have emerged for the collection and storage of umbilical cord blood: 1) public banks and 2) private banks. The benefits and limitations of public versus private umbilical cord blood banking should be reviewed with the patient because they serve different purposes. This patient discussion also should include the concept of autologous and allogeneic use of umbilical cord blood. Umbilical cord blood collected from a neonate cannot be used to treat a genetic disease or malignancy in that same individual (autologous transplant) because stored cord blood contains the same genetic variant or premalignant cells that led to the condition being treated. There is no current evidence to support the use of an autologous umbilical cord blood sample in regenerative medicine. Patients should be made aware of the quality control and regulatory organizations that provide oversight for the process of umbilical cord collection and storage. Umbilical cord blood collection should not compromise obstetric or neonatal care or alter routine practice of delayed umbilical cord clamping with the rare exception of medical indications for directed donation. Therefore, it is important to inform patients that the medical condition of the woman or neonate may prevent adequate umbilical cord blood collection. This document is updated with a statement that the routine use of private cord blood banking is not supported by available evidence and that public banking is the recommended method of obtaining cord blood. In addition, the importance of contribution from all ethnicities and races to public banks is highlighted.

ACOG Committee Opinion No. 771 Summary: Umbilical Cord Blood Banking

Since the first successful umbilical cord blood transplant in 1988, it has been estimated that more than 35,000 transplants have been performed in children and adults for the correction of inborn errors of metabolism, hematopoietic malignancies, and genetic disorders of the blood and immune system. Two types of banks have emerged for the collection and storage of umbilical cord blood: 1) public banks and 2) private banks. The benefits and limitations of public versus private umbilical cord blood banking should be reviewed with the patient because they serve different purposes. This patient discussion also should include the concept of autologous and allogeneic use of umbilical cord blood. Umbilical cord blood collected from a neonate cannot be used to treat a genetic disease or malignancy in that same individual (autologous transplant) because stored cord blood contains the same genetic variant or premalignant cells that led to the condition being treated. There is no current evidence to support the use of an autologous umbilical cord blood sample in regenerative medicine. Patients should be made aware of the quality control and regulatory organizations that provide oversight for the process of umbilical cord collection and storage. Umbilical cord blood collection should not compromise obstetric or neonatal care or alter routine practice of delayed umbilical cord clamping with the rare exception of medical indications for directed donation. Therefore, it is important to inform patients that the medical condition of the woman or neonate may prevent adequate umbilical cord blood collection. This document is updated with a statement that the routine use of private cord blood banking is not supported by available evidence and that public banking is the recommended method of obtaining cord blood. In addition, the importance of contribution from all ethnicities and races to public banks is highlighted.

Human cord blood-derived viral pathogens as the potential threats to the hematopoietic stem cell transplantation safety: A mini review.

Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) and potential alternative for bone marrow transplantation for patients who lack human leukocyte antigen (HLA)-matched donors. The main practical advantages of UCB over other HSC sources are the immediate availability, lower incidence of graft-versus-host disease, minimal risk to the donor, and lower requirement for HLA compatibility. However, the use of UCB is limited by delayed engraftment and poor immune reconstitution, leading to a high rate of infection-related mortality. Therefore, severe infectious complications, especially due to viral pathogens remain the leading cause of morbidity and mortality during the post-UCB transplantation (UCBT) period. In this context, careful screening and excluding the viral-contaminated UCB units might be an effective policy to reduce the rate of UCBT-related infection and mortality. Taken together, complete prevention of the transmission of donor-derived viral pathogens in stem cell transplantation is not possible. However, having the knowledge of the transmission route and prevalence of viruses will improve the safety of transplantation. To the best of our knowledge, there are few studies that focused on the risk of virus transmission through the UCB transplant compared to other HSC sources. This review summarizes the general aspects concerning the prevalence, characteristics, and risk factors of viral infections with a focus on the impact of viral pathogens on cord blood transplantation safety.

Umbilical cord blood as a source for red-blood-cell transfusion in neonatology: a systematic review.

The prevention and treatment of anaemia in newborn patients made tremendous progress in the last decades. However, red-blood-cell (RBC) transfusions remain unavoidable in many neonates candidate to surgery and especially in preterm infants. In particular, anaemia occurring in neonates born at extremely low gestational age is actually severe and frequently requires transfusions. Several approaches have been explored to prevent or even to reduce the threshold and the frequency of RBC transfusions. Among these, umbilical cord blood (UCB) collection and processing to obtain RBC components for autologous or allogeneic transfusion have been extensively investigated. In this systematic review, we revised the literature concerning the use of UCB for either autologous or allogeneic transfusion purposes and we illustrated the rationale for a transfusion therapy tailored to extremely preterm neonates, based on RBC concentrates from allogeneic UCB donations.

Chondrogenic Differentiation of Defined Equine Mesenchymal Stem Cells Derived from Umbilical Cord Blood for Use in Cartilage Repair Therapy.

Cartilage engineering is a new strategy for the treatment of cartilage damage due to osteoarthritis or trauma in humans. Racehorses are exposed to the same type of cartilage damage and the anatomical, cellular, and biochemical properties of their cartilage are comparable to those of human cartilage, making the horse an excellent model for the development of cartilage engineering. Human mesenchymal stem cells (MSCs) differentiated into chondrocytes with chondrogenic factors in a biomaterial appears to be a promising therapeutic approach for direct implantation and cartilage repair. Here, we characterized equine umbilical cord blood-derived MSCs (eUCB-MSCs) and evaluated their potential for chondrocyte differentiation for use in cartilage repair therapy. Our results show that isolated eUCB-MSCs had high proliferative capacity and differentiated easily into osteoblasts and chondrocytes, but not into adipocytes. A three-dimensional (3D) culture approach with the chondrogenic factors BMP-2 and TGF-β1 potentiated chondrogenic differentiation with a significant increase in cartilage-specific markers at the mRNA level (Col2a1, Acan, Snorc) and the protein level (type II and IIB collagen) without an increase in hypertrophic chondrocyte markers (Col10a1 and Mmp13) in normoxia and in hypoxia. However, these chondrogenic factors caused an increase in type I collagen, which can be reduced using small interfering RNA targeting Col1a2. This study provides robust data on MSCs characterization and demonstrates that eUCB-MSCs have a great potential for cartilage tissue engineering.

Modeling Human Antitumor Responses In Vivo Using Umbilical Cord Blood-Engrafted Mice.

Mice engrafted with human immune cells offer powerful in vivo model systems to investigate molecular and cellular processes of tumorigenesis, as well as to test therapeutic approaches to treat the resulting cancer. The use of umbilical cord blood mononuclear cells as a source of human immune cells for engraftment is technically straightforward, and provides T lymphocytes and autologous antigen-presenting cells (including B cells, monocytes, and DCs) that bear cognate antigen presenting molecules. By using a human-specific oncogenic virus, such as Epstein-Barr virus, de novo neoplastic transformation of the human B cells can be induced in vivo in a manner that models progressive stages of tumorigenesis from nascent neoplasia to the establishment of vascularized tumor masses with an immunosuppressive environment. Moreover, since tumorigenesis occurs in the presence of autologous T cells, this type of system can be used to investigate how T cells become suppressed during tumorigenesis, and how immunotherapies counteract immunosuppression. This minireview will provide a brief overview of the use of human umbilical cord blood transplanted into immunodeficient murine hosts to model antitumor responses.

Review: Umbilical Cord Stem Cells

The use of umbilical cord blood as an alternative to bone marrow as a source of haematopoietic stem cells for the treatment of certain diseases has been on an increase since the first transplantation of umbilical cord-derived stem cells in 1988. In this paper, 6 of the latest case studies about the use of such stem cells have been discussed and are used as evidence to confirm the potential use of the umbilical cord as a source of haematopoietic stem cells for transplantation as treatment to various diseases. The debate over whether umbilical cord blood should be stored and why public banking facilities are preferred over those that are private have also been discussed in this paper.

Phase 2 Trials with Mgta-456, Single Cord Blood Units (CBU) Expanded with an Aryl Hydrocarbon Receptor (AHR) Antagonist, Demonstrate Uniform Engraftment and Rapid Hematopoietic Recovery in Patients Following Myeloablative or Non-Myeloablative Conditioning

Background. The use of umbilical cord blood (UCB) in transplant has been limited by the low number of CD34+ cells, resulting in prolonged periods of cytopenia for patients and high risk of graft failure, thereby restricting its widespread application. MGTA-456 is the hematopoietic cell product after cord blood CD34+ cells are placed in expansion culture for 15 days with an aryl hydrocarbon receptor (AHR) antagonist in the presence of SCF, Flt-3L, IL-6 and TPO. In a prior Phase 1/2 safety study, 18 patients received MGTA-456, its accompanying CD34negfraction and a larger, unexpanded UCB unit. All patients engrafted at a median of 14.5 days (range, 7-23), significantly faster than similarly treated historical controls (p<0.01). Based on these results, two Phase 2 studies were initiated to evaluate the effectiveness of MGTA-456 as a stand-alone graft after myeloablative conditioning (MAC) or non-myeloablative conditioning (NMAC).Patients and Methods : Twenty patients with high-risk hematologic malignancy and a partially HLA-matched CBU were enrolled; 10 were treated with cyclophosphamide (CY) 120 mg/kg, fludarabine (FLU) 75 mg/m2 and total body irradiation (TBI) 1320 cGy (MAC) and 10 with CY 50 mg/kg, FLU 200 mg/m2 and TBI 200 cGy (NMAC). All patients received cyclosporine and mycophenolate mofetil post-transplant immunoprophylaxis. Expansion was low in 2 UCB units, therefore 18 patients received MGTA-456 and its CD34neg fraction.Results : Expansion culture yielded a median of 1,227 x 106 CD34+ cells (range, 201-8969) as compared to the input number of 4.2 x 106 (range, 1.4-16.3) after CD34 selection - a 324-fold (range, 42-1643) expansion of CD34+ cells. As transplant results vary by intensity of the conditioning, patient outcomes were compared to similarly treated historical cohorts between 2006 and 2015 (n=151 MAC; n=132 NMAC). For both groups, demographics were similar except for more recent year of transplant for recipients of MGTA-456. For recipients of MAC, MGTA-456 engrafted in all patients at a median of 14 days (range, 7-32) as compared to 89% engraftment at a median of 23 days (range, 19-31) in the control population (p<0.01, see Figure 1). Complete chimerism was rapid for both myeloid and T cells with no late graft failures; the longest follow-up was 5.6 years in recipients of MGTA-456. For recipients of NMAC, MGTA-456 also engrafted in all patients at a median of 7 days (range, 6-14) as compared to 94% engraftment at a median of 15 days (range, 7-22). In contrast to complete chimerism seen after MAC, chimerism is often mixed for the first month in both myeloid and T cells after NMAC. Compared to the historical cohort, recipients of MGTA-456 had more rapid chimerism after NMAC. CD34 cell dose correlates with speed of recovery but only in recipients with MAC; in recipients of NMAC, recovery is uniformly rapid regardless of CD34 cell dose. Additionally, immune recovery as measured by an absolute CD4 count >200/uL was achieved at day 60 (median) in recipients of MGTA-456 regardless of conditioning regimen. Results were also encouraging for other transplant outcomes. For recipients of MGTA-456 compared to the historical cohort after MAC, incidence of acute GVHD (aGVHD) grade 3-4 was 22% vs 24%; chronic GVHD (cGVHD), 11% vs 21%; transplant-related mortality (TRM), 11% vs 34%; and overall survival (OS), 67% vs 55%. After NMAC, results were similar between cohorts except for a higher risk of aGVHD in recipients of MGTA-456 (aGVHD 3-4, 43% vs 15%; cGVHD, 0% vs 19%; TRM, 22% vs 20%; and OS, 44% vs 49%). The increased rate of aGVHD in the NMAC cohort likely reflects non-compliance with prescribed GVHD immunoprophylaxis in 2 of 9 recipients.Conclusion : In these studies, MGTA-456 significantly accelerated hematopoietic recovery and abrogated the engraftment barrier typically associated with UCB transplantation. The marked expansion of CD34+ cells in MGTA-456 suggests that a significant number of patients will have an adequate single CBU and better HLA matched graft since a greater proportion of the cord blood inventory will be available irrespective of weight. Given these promising results, additional studies are being planned. [Display omitted] DisclosuresWagner:Novartis: Research Funding; Magenta Therapeutics: Research Funding. Brunstein:Novartis: Research Funding; Magenta Therapeutics: Research Funding. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties; Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. McKenna:Magenta Therapeutics: Research Funding; Novartis: Research Funding. Sanna:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Bleul:Hoffmann-La Roche AG: Employment. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties.

In Vitro Hematopoietic Reprogramming and Generation of Hematopoietic Stem Cells

Hematopoietic stem cell (HSC) transplantation is widely used to treat a variety of disorders. Despite advances in the use of umbilical cord blood and mobilized stem cells, donor material remains limited. This is due to insufficient numbers of stem cells in cord blood, poor mobilization, and the lack of ethnic diversity to provide sufficient genetically matched material. Despite intensive efforts there has been limited success in generating transplantable HSCs from pluripotent stem cells (PSCs). Clearly, alternative approaches are necessary. Directly programmed hematopoietic stem/progenitor cells would provide an unlimited patient-specific source for cell replacement and genetic correction therapies as well as a platform for the future generation of patient specific therapeutics and blood products. In 2013 we demonstrated direct reprogramming of mouse fibroblasts into clonogenic hematopoietic progenitors with just four transcription factors (TFs), Gata2, Gfi1b, cFos and Etv6 (Pereira et al 2013). These four TFs induce a dynamic, multi-stage hemogenic process that progresses through an endothelial-like intermediate. As such, it appears to recapitulate definitive developmental hematopoiesis in vitro. We now have strong evidence that a similar hemogenic process can be optimally induced in human fibroblasts with Gata2, Gfi1b, and cFos. These reprogrammed cells are able to multi-lineage repopulate NSG mice. Therefore we maintain that in vitro reprogramming provides a tractable system to address the underlying molecular mechanisms of hemogenesis not possible in primary cells. We have now studied how the TFs bind DNA and initiate a molecular program that changes the epigenetic landscape to allow a change in cell fate. The studies to date have revealed cooperative binding of two of the factors to the binding motif of the other causing simultaneous silencing of fibroblast genes and activation of endothelial and hematopoietic genes. Pereira CF, Chang B, Qiu J, Niu X, Papatsenko D, Hendry CE, Clark NR, Nomura-Kitabayashi A, Kovacic JC, Ma'ayan A, Schaniel C, Lemischka IR, Moore K. Induction of a Hemogenic Program in Mouse Fibroblasts. Cell Stem Cell. 2013;13:205-218. Disclosures No relevant conflicts of interest to declare.