Planned Granulocyte Colony-Stimulating Factor Adversely Impacts Survival after Allogeneic Hematopoietic Cell Transplantation Performed with Thymoglobulin for Myeloid Malignancy.

The in vivo depletion of recipient and donor T lymphocytes using antithymocyte globulin (ATG; Thymoglobulin) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce the incidence of both graft failure and graft-versus-host disease (GVHD). However, excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising antitumor effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lymphotoxicity. This study aimed to investigate the effect of an interaction between ATG and post-transplantation granulocyte colony-stimulating factor (G-CSF) on allogeneic HCT outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. We studied patients age ≥18 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who received Thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT between 2010 and 2018. The effect of planned G-CSF that was started between pretransplantation day 3 and post-transplantation day 12 was studied in comparison with transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes at 1 year after transplantation. A total of 874 patients met the study eligibility criteria, of whom 459 (53%) received planned G-CSF. HCT with planned G-CSF was associated with a significantly increased risk for nonrelapse mortality (NRM) (hazard ratio [HR] 2.03; P <.0001; 21% versus 12%) compared to HCT without G-CSF. The 6-month incidence of viral infection was higher with G-CSF (56% versus 47%; P = .007), with a particular increase in Epstein-Barr virus infections (19% versus 11%; P = .002). The observed higher NRM with planned G-CSF led to lower overall survival (HR, 1.52; P = .0005; 61% versus 72%). There was no difference in GVHD risk between the treatment groups. We performed 2 subgroup analyses showing that our findings held true in patients age ≥50 years and in centers where G-CSF was used in some, but not all, patients. In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplantation resulted in a 2-fold increase in NRM and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplantation period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks.

HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis.

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.

Standardization, workforce development and advocacy in cell and gene therapies: a summary of the 2020 Regenerative Medicine InterCHANGE.

Cell and gene therapy is a promising and disruptive new field of medicine for diseases lacking effective treatments. Collaboration among stakeholders has become critically important as investigators, health care providers, manufacturers, couriers, data registries, regulators and payers all become more invested in the success of this field. Many organizations have collaborated with each other to increase clarity, advocate for improvements and share lessons learned. These efforts appear to be making an impact, although the potential for duplicative efforts could slow progress. The second Regenerative Medicine InterCHANGE, hosted by the Foundation for the Accreditation of Cellular Therapy, took place at the Phacilitate Leaders World/World Stem Cell Summit conference in Miami, Florida, on January 24, 2020. Participants from several organizations outlined needs to advance cell and gene therapies. Efforts to address these include standardization, workforce development and advocacy. This article summarizes the major challenges and opportunities discussed during the InterCHANGE.

Myeloablative vs reduced intensity T-cell-replete haploidentical transplantation for hematologic malignancy.

In the absence of prospective studies that examine the effect of conditioning regimen intensity after T-cell-replete haploidentical transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), a retrospective cohort analysis was performed. Of the 1325 eligible patients (AML, n = 818; ALL, n = 286; and MDS, n = 221), 526 patients received a myeloablative regimen and 799 received a reduced-intensity regimen. Graft-versus-host disease prophylaxis was uniform with posttransplant cyclophosphamide, a calcineurin inhibitor, and mycophenolate mofetil. The primary end point was disease-free survival. Cox regression models were built to study the effect of conditioning regimen intensity on transplant outcomes. For patients aged 18 to 54 years, disease-free survival was lower (hazard ratio [HR], 1.34; 42% vs 51%; P = .007) and relapse was higher (HR, 1.51; 44% vs 33%; P = .001) with a reduced-intensity regimen compared with a myeloablative regimen. Nonrelapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival (HR, 0.97; 37% vs 43%; P = .83) and relapse (HR, 1.32; 42% vs 31%; P = .11) did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens (HR, 0.64; 20% vs 31%; P = .02). Myeloablative regimens are preferred for AML, ALL, and MDS; reduced-intensity regimens should be reserved for those unable to tolerate myeloablation.

Ex vivo expansion of cord blood-derived endothelial cells using a novel xeno-free culture media.

AIM: Endothelial cells (ECs), isolated from peripheral blood (PB), bone marrow (BM) and cord blood (CB), are limited in numbers and expansion has had limited success. We used a novel serum-free medium (EndoGo) to evaluate effects on ex vivo expansion of CB-derived ECs. MATERIALS & METHODS: Flow cytometry and matrigel were used to determine expansion of ECs and for determination of the EC progenitor cell. RESULTS: EndoGo™-containing cultures demonstrated superior expansion and stimulated proliferation of two distinct subpopulations, CD34+CD31+ and CD34-CD31+, which exhibited different morphology, phenotype and function. EndoGo also expanded the CB endothelial progenitor cells from freshly isolated CB. CONCLUSION: These findings demonstrate the potential of EndoGo to expand CB ECs, which could generate increased numbers of ECs for therapeutic applications.

TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization.

Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies. This resistance is related to the molecular genetic heterogeneity in MM cells as well as to the contributions from the BM, which is one of the key determinants of treatment outcome. Our previous studies using fluorescent tracers revealed that MM heterogeneity is correlated with the presence of quiescent stem-like cancer cells, which prefer to reside within the osteoblastic niche of the BM. In this report, we identified a novel protein, tripartite motif containing 44 (TRIM44), which is overexpressed in the osteoblastic niche of the BM, enabling MM cells to compete with HSCs for niche support. TRIM44 expression in MM cells promoted cell quiescence but increased bone destruction in xenograft mice, similar to what is observed in MM patients. TRIM44 functions as a deubiquitinase for hypoxia inducible factor-1α (HIF-1α), which stabilizes HIF-1α expression during hypoxia and normoxia. Stabilized HIF-1α stimulates MM cell growth and survival during hypoxia. Our work is the first report to reveal signaling in quiescent MM cells and the functions of TRIM44.

Third party, umbilical cord blood derived regulatory T-cells for prevention of graft versus host disease in allogeneic hematopoietic stem cell transplantation: feasibility, safety and immune reconstitution.

Incubation of umbilical cord blood (UCB) derived regulatory T-cells (Tregs) with fucosyltransferase enzyme improves their ability to home to the target tissue to prevent graft vs. host disease (GVHD). We report results of 5 patients (Double UCB Transplant, n=2; Peripheral Blood Matched Unrelated Donor Transplant, n=3) who received UCB-Tregs (Dose level = 1×106/kg), infused one day prior to the donor graft. All patients received their designated UCB-Treg dose without any infusion reaction. The ratio of conventional T-cells in donor graft was at least 10 times higher than infused UCB-Tregs (ratio range, 12-356). All patients engrafted at median of 13 days (range, 8-17 days). One patient died due to brain hemorrhage on day 45. A bi-modal increase of plasma IL-10 level occurred on day 7 and day 21 and notably, plasma IL-2 level dropped significantly in all patients at Day 7. All evaluable patients developed ≥grade II acute GVHD and at 1 year follow up, all were alive and without evidence of disease relapse. No increase in the chronic GVHD biomarkers (REG3a and Elafin) was observed at day 7. At the time of last follow up, all evaluable patients were off immune-suppression. Stage 2 of this clinical trial examining UCB-Treg at dose level= 1×107/kg is currently underway.

Related donor transplants: has posttransplantation cyclophosphamide nullified the detrimental effect of HLA mismatch?

We sought to identify whether posttransplantation cyclophosphamide (PT-Cy) reduces or eliminates the detrimental impact of HLA mismatching on outcomes of HLA-haploidentical related donor transplantation for acute leukemia. Data from 2143 donor-recipient pairs (n = 218 haploidentical sibling; n = 218 offspring; n = 1707 HLA-matched sibling) with acute myeloid or lymphoblastic leukemia were studied. All received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis while high-dose PT-Cy was also given to recipients of haploidentical transplant. Patient age correlated with donor-recipient relationship: haploidentical siblings donated to patients aged 18 to 54 years whereas offspring donated to patients aged 55 to 76 years. Therefore, transplant outcomes were examined separately in the 2 patient age groups. In patients aged 18 to 54 years, there were no significant differences in outcomes except chronic GVHD, which was lower after haploidentical sibling compared to HLA-matched sibling transplant (hazard ratio [HR], 0.63; P < .001). In patients aged 55 to 76 years, despite lower chronic GVHD (HR, 0.42; P < .001), graft failure (14% vs 6%; P = .003), nonrelapse mortality (HR, 1.48; P = .02), and overall mortality (HR, 1.32; P = .003) were higher after transplant from offspring compared with an HLA-matched sibling. These data demonstrate a superior outcome in older recipients when using an HLA-matched sibling instead of offspring, although there were differences in transplant platforms (GVHD prophylaxis and graft type) between the 2 groups. Validation of these findings requires a prospective randomized trial wherein the transplant platforms can be closely matched.

International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials.

Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an "open-access" manner, such as through publication or database collection.

Current perspectives on the use of ancillary materials for the manufacture of cellular therapies.

Continued growth in the cell therapy industry and commercialization of cell therapies that successfully advance through clinical trials has led to increased awareness around the need for specialized and complex materials utilized in their manufacture. Ancillary materials (AMs) are components or reagents used during the manufacture of cell therapy products but are not intended to be part of the final products. Commonly, there are limitations in the availability of clinical-grade reagents used as AMs. Furthermore, AMs may affect the efficacy of the cell product and subsequent safety of the cell therapy for the patient. As such, AMs must be carefully selected and appropriately qualified during the cell therapy development process. However, the ongoing evolution of cell therapy research, limited number of clinical trials and registered cell therapy products results in the current absence of specific regulations governing the composition, compliance, and qualification of AMs often leads to confusion by suppliers and users in this field. Here we provide an overview and interpretation of the existing global framework surrounding AM use and investigate some common misunderstandings within the industry, with the aim of facilitating the appropriate selection and qualification of AMs. The key message we wish to emphasize is that in order to most effectively mitigate risk around cell therapy development and patient safety, users must work with their suppliers and regulators to qualify each AM to assess source, purity, identity, safety, and suitability in a given application.

Isolation of a novel chronic lymphocytic leukemic (CLL) cell line and development of an in vivo mouse model of CLL.

Leukemic cell lines have become important tools for studies of disease providing a monoclonal cell population that can be extensively expanded in vitro while preserving leukemic cellular characteristics. However, studies of chronic lymphocytic leukemia (CLL) have been impeded in part by the lack of continuous human cell lines. CLL cells have a high spontaneous apoptosis rate in vitro and exhibit minimal proliferation in xenograft models. Therefore, there is a need for development of primary CLL cell lines and we describe the isolation of such a line from the bone marrow of a CLL patient (17p deletion and TP53 mutation) which has been in long term culture for more than 12 months with continuous proliferation. The CLL cell line (termed MDA-BM5) which was generated in vitro with continuous co-culture on autologous stromal cells is CD19+CD5+ and shows an identical pattern of somatic hypermutation as determined in the patient's bone marrow (BM), confirming the origin of the cells from the original CLL clone. MDA-BM5 cells were readily transplantable in NOD/SCID gamma null mice (NSG) with disease developing in the BM, liver and spleen. BM cells from quaternary serial transplantation in NSG mice demonstrated the presence of CD19+CD5+ cells with Ig restricted to lambda which is consistent with the original patient cells. These studies describe a new CLL cell line from a patient with del(17p) that provides a unique model for in vitro and in vivo studies.

Differential properties of human stromal cells from bone marrow, adipose, liver and cardiac tissues.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs), derived from several tissues including bone marrow and adipose tissue, are being evaluated in clinical trials for a range of diseases. Virtually all tissues of the body contain stromal cells, yet it is unknown whether these sources are similar in phenotype and function. METHODS: We have isolated stromal cells from several human tissues including bone marrow (BM-MSCs), heart (heart stroma, HS), adipose (adipose stroma, AS) and liver (liver stroma, LS) and compared the morphology, phenotype and functional properties of these stromal cell populations. RESULTS: The cellular phenotype of each population was identical, namely, CD105+, CD73+, CD90+, CD34- and CD45-. In addition, morphology and differentiation potential were comparable. Co-culture studies revealed similar supportive potential of BM-MSCs, AS and LS with hematopoietic cells or tumor cells. In contrast, significant inhibition of proliferation of both cells types was obtained with HS, with significant loss of viability with tumor cells, demonstrating a unique functional property of HS with regard to tumor cell proliferation. CONCLUSIONS: Although stromal cells from different tissues have similar morphology and phenotype, their functional properties vary, requiring critical evaluation of stromal cells before use in non-homologous settings. HS may play a key role in inhibiting proliferation of tumor cells in the heart, providing the reason for the low occurrence of tumor development. Given the tumor-supportive property of BM-MSCs and AS, the use of these cells in cardiac tissue may result in replacement of a tumor-inhibitory stroma with a tumor-supportive microenvironment.

Novel clinical uses for cord blood derived mesenchymal stromal cells.

Regenerative medicine offers new hope for many debilitating diseases that result in damage to tissues and organs. The concept is straightforward with replacement of damaged cells with new functional cells. However, most tissues and organs are complex structures involving multiple cell types, supportive structures, a microenvironment producing cytokines and growth factors and a vascular system to supply oxygen and other nutrients. Therefore repair, particularly in the setting of ischemic damage, may require delivery of multiple cell types providing new vessel formation, a new microenvironment and functional cells. The field of stem cell biology has identified a number of stem cell sources including embryonic stem cells and adult stem cells that offer the potential to replace virtually all functional cells of the body. The focus of this article is a discussion of the potential of mesenchymal stromal cells (MSCs) from cord blood (CB) for regenerative medicine approaches.

Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation.

Delayed engraftment is a major limitation of cord blood transplantation (CBT), due in part to a defect in the cord blood (CB) cells' ability to home to the bone marrow. Because this defect appears related to low levels of fucosylation of cell surface molecules that are responsible for binding to P- and E-selectins constitutively expressed by the marrow microvasculature, and thus for marrow homing, we conducted a first-in-humans clinical trial to correct this deficiency. Patients with high-risk hematologic malignancies received myeloablative therapy followed by transplantation with 2 CB units, one of which was treated ex vivo for 30 minutes with the enzyme fucosyltransferase-VI and guanosine diphosphate fucose to enhance the interaction of CD34(+) stem and early progenitor cells with microvessels. The results of enforced fucosylation for 22 patients enrolled in the trial were then compared with those for 31 historical controls who had undergone double unmanipulated CBT. The median time to neutrophil engraftment was 17 days (range, 12-34 days) compared with 26 days (range, 11-48 days) for controls (P = .0023). Platelet engraftment was also improved: median was 35 days (range, 18-100 days) compared with 45 days (range, 27-120 days) for controls (P = .0520). These findings support ex vivo fucosylation of multipotent CD34(+) CB cells as a clinically feasible means to improve engraftment efficiency in the double CBT setting. The trial is registered to www.clinicaltrials.gov as #NCT01471067.

Ex vivo fucosylation of third-party human regulatory T cells enhances anti-graft-versus-host disease potency in vivo.

Adoptive therapy with regulatory T cells (Tregs) to prevent graft-versus-host disease (GVHD) would benefit from a strategy to improve homing to the sites of inflammation. We hypothesized that adding fucose to human Tregs, forming the Sialyl Lewis X moiety on P-selectin glycoprotein ligand-1, would improve their trafficking pattern. The selectin pathway recruiter, α-1,3-fucosyltransferase-VI enzyme, significantly increased Treg surface fucosylation (66% vs 8%). In a xenogenic GVHD mouse model, fucosylated Tregs showed prolonged periods of in vivo persistence. When given at a lower dose compared with the untreated Tregs, the murine recipients of fucosylated Tregs maintained weight, had ameliorated clinical GVHD, and improved survival (70% vs 30%; P < .0001). These preclinical data indicate that fucosylated human Tregs is an effective strategy for prevention of GVHD and, as such, warrants consideration for future clinical trials.

Phenotypic and functional comparison of mobilized peripheral blood versus umbilical cord blood megakaryocyte populations.

BACKGROUND AIMS: Hematopoietic stem cell transplantation of mobilized peripheral blood progenitor cell (PBPC) products results in rapid platelet engraftment, whereas the use of cord blood (CB) shows significant delays. The difference in the quality and number of megakaryocyte (MK) progenitors that may be responsible for the delay in platelet engraftment has not been fully defined. The objective of this study was to quantify the cells of the MK lineage in PBPC and CB products to determine whether potential differences exist. METHODS: We examined PBPC or CB for differences in surface markers and subpopulations as well as polyploidization status within the MK lineage. Colony-forming assays were used to determine whether differences exist in the clonogenic MK progenitor cell. Finally, we transplanted PBPC and CB mononuclear cells into NOD/SCID/IL2Rγ-/- (NSG) mice to study platelet engraftment rates. RESULTS: Equivalent MK populations and polyploidization was observed in PBPCs and CB. MK progenitors were present only in CD34+ cells and had little difference in colony growth between PBPC and CB. Additionally, MK subpopulations were similar in either product with a slightly more progenitor-enriched phenotype in CB. Finally, when PBPC or CB was transplanted at similar doses, equivalent platelet engraftment rates were observed. CONCLUSIONS: PBPC and CB contain similar frequencies of MK populations, and, when transplanted in comparable doses, CB is as effective as PBPCs in producing platelet engraftment in vivo. Understanding the differences in MK populations between PBPC and CB could help generate protocols to improve platelet engraftment after CB transplantation.

Bone marrow-derived c-kit+ cells attenuate neonatal hyperoxia-induced lung injury.

Recent studies suggest that bone marrow (BM)-derived stem cells have therapeutic efficacy in neonatal hyperoxia-induced lung injury (HILI). c-kit, a tyrosine kinase receptor that regulates angiogenesis, is expressed on several populations of BM-derived cells. Preterm infants exposed to hyperoxia have decreased lung angiogenesis. Here we tested the hypothesis that administration of BM-derived c-kit(+) cells would improve angiogenesis in neonatal rats with HILI. To determine whether intratracheal (IT) administration of BM-derived c-kit(+) cells attenuates neonatal HILI, rat pups exposed to either normobaric normoxia (21% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to P15 were randomly assigned to receive either IT BM-derived green fluorescent protein (GFP)(+) c-kit(-) cells (PL) or BM-derived GFP(+) c-kit(+) cells on P8. The effect of cell therapy on lung angiogenesis, alveolarization, pulmonary hypertension, vascular remodeling, cell proliferation, and apoptosis was determined at P15. Cell engraftment was determined by GFP immunostaining. Compared to PL, the IT administration of BM-derived c-kit(+) cells to neonatal rodents with HILI improved alveolarization as evidenced by increased lung septation and decreased mean linear intercept. This was accompanied by an increase in lung vascular density, a decrease in lung apoptosis, and an increase in the secretion of proangiogenic factors. There was no difference in pulmonary vascular remodeling or the degree of pulmonary hypertension. Confocal microscopy demonstrated that 1% of total lung cells were GFP(+) cells. IT administration of BM-derived c-kit(+) cells improves lung alveolarization and angiogenesis in neonatal HILI, and this may be secondary to an improvement in the lung angiogenic milieu.

Concise review: umbilical cord blood transplantation: past, present, and future.

Allogeneic hematopoietic stem cell transplantation is an important treatment option for fit patients with poor-risk hematological malignancies; nevertheless, the lack of available fully matched donors limits the extent of its use. Umbilical cord blood has emerged as an effective alternate source of hematopoietic stem cell support. Transplantation with cord blood allows for faster availability of frozen sample and avoids invasive procedures for donors. In addition, this procedure has demonstrated reduced relapse rates and similar overall survival when compared with unrelated allogeneic hematopoietic stem cell transplantation. The limited dose of CD34-positive stem cells available with single-unit cord transplantation has been addressed by the development of double-unit cord transplantation. In combination with improved conditioning regimens, double-unit cord transplantation has allowed for the treatment of larger children, as well as adult patients with hematological malignancies. Current excitement in the field revolves around the development of safer techniques to improve homing, engraftment, and immune reconstitution after cord blood transplantation. Here the authors review the past, present, and future of cord transplantation.