Novel cord blood transplant therapies.
Ontology highlight
ABSTRACT:
SUBMITTER: Shpall EJ
PROVIDER: S-EPMC4213144 | biostudies-literature | 2011 Jan
REPOSITORIES: biostudies-literature
Publications
Novel cord blood transplant therapies.
Shpall Elizabeth J EJ Bollard Catherine M CM Brunstein Claudio C
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20101015 1 Suppl
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Project description:Umbilical cord blood transplant (CBT) has traditionally been associated with slower engraftment of neutrophils, delayed immune reconstitution and consequently higher risk of infections as compared with peripheral blood progenitor cell (PBPC) or bone marrow (BM) transplants. This is primarily due to low numbers of total nucleated cells (TNCs) and the naive nature of CB immune cells. The use of double unit CB transplant (DCBT) increases the total cell dose in the graft, but it still does not produce as rapid engraftment as seen with PBPC or even BM transplants. Herein, we discuss strategies to improve engraftment after CBT. We describe methods of (I) expansion of CB graft ex vivo to increase the total cell dose; and (II) enhancement of BM homing capability of CB progenitor cells; (III) ex vivo expansion of CB derived T cells for improving T cell function against viruses, tumors and protection from graft versus host disease (GVHD). With these novel approaches, engraftment after CBT is now reaching levels comparable to that of other graft types.
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| S-EPMC6355502 | biostudies-literature
Project description:ObjectiveTo model the long-term clinical and economic outcomes of potential cord blood therapy in autism spectrum disorder (ASD).Study designMarkov microsimulation of ASD over the lifespan was used to compare two strategies: 1) standard of care (SOC), including behavioral and educational interventions, and 2) novel cord blood (CB) intervention in addition to SOC. Input data reflecting behavioral outcomes included baseline Vineland Adaptive Behavior Scale (VABS-3), monthly VABS-3 changes, and CB intervention efficacy on adaptive behavior based on a randomized, placebo-controlled trial (DukeACT). Quality-adjusted life-years (QALYs) were correlated to VABS-3. Costs for children with ASD ($15,791, ages 2-17 years) and adults with ASD ($56,559, ages 18+ years), and the CB intervention (range $15,000-45,000) were incorporated. Alternative CB efficacy and costs were explored.ResultsWe compared model-projected results to published data on life-expectancy, mean VABS-3 changes, and lifetime costs. Undiscounted lifetime QALYs in the SOC and CB strategies were 40.75 and 40.91. Discounted lifetime costs in the SOC strategy were $1,014,000, and for CB ranged from $1,021,000-$1,058,000 with CB intervention cost ($8,000-$45,000). At $15,000 cost, CB was borderline cost-effective (ICER = $105,000/QALY). In one-way sensitivity analysis, CB cost and efficacy were the most influential parameters on CB ICER. CB intervention was cost-effective at costs<$15,000 and efficacies ≥2.0. Five-year healthcare payer projected budgetary outlays at a $15,000 CB cost were $3.847B.ConclusionsA modestly effective intervention designed to improve adaptive behavior in autism can be cost-effective under certain circumstances. Intervention cost and efficacy most affected the cost-effectiveness results and should be targeted to increase economic efficiency.
| S-EPMC10112778 | biostudies-literature
Project description:Hematopoietic cell transplants using stem cells from umbilical cord blood are used worldwide for the treatment of malignant and non-malignant disorders. Transplant procedures from this stem cell source have shown promising outcomes in successfully treating various hematologic, immunologic, malignant, and inherited metabolic disorders. Rapid availability of these stem cells is an important advantage over other unrelated donor transplants, especially in situations where waiting can adversely affect the prognosis. The umbilical cord blood is rich in CD34+ stem cells, though with a limited cell dose and usually takes longer to engraft. Limitations around this have been addressed by in vivo and ex vivo expansion techniques as well as enhanced engraftment kinetics. Development of adoptive immunotherapy using other components of umbilical cord blood such as regulatory T cells, virus-specific T cells, and natural killer cells has further transformed the field and enhanced the utility of umbilical cord blood unit.
| S-EPMC7567024 | biostudies-literature
Project description:Adoptive transfer of virus-specific T cells (VSTs) has been shown to be safe and effective in stem cell transplant recipients. However, the lack of virus-experienced T cells in donor cord blood (CB) has prevented the development of ex vivo expanded donor-derived VSTs for recipients of this stem cell source. Here we evaluated the feasibility and safety of ex vivo expansion of CB T cells from the 20% fraction of the CB unit in pediatric patients receiving a single CB transplant (CBT). In 2 clinical trials conducted at 2 separate sites, we manufactured CB-derived multivirus-specific T cells (CB-VSTs) targeting Epstein-Barr virus (EBV), adenovirus, and cytomegalovirus (CMV) for 18 (86%) of 21 patients demonstrating feasibility. Manufacturing for 2 CB-VSTs failed to meet lot release because of insufficient cell recovery, and there was 1 sterility breach during separation of the frozen 20% fraction. Delayed engraftment was not observed in patients who received the remaining 80% fraction for the primary CBT. There was no grade 3 to 4 acute graft-versus-host disease (GVHD) associated with the infusion of CB-VSTs. None of the 7 patients who received CB-VSTs as prophylaxis developed end-organ disease from CMV, EBV, or adenovirus. In 7 patients receiving CB-VSTs for viral reactivation or infection, only 1 patient developed end-organ viral disease, which was in an immune privileged site (CMV retinitis) and occurred after steroid therapy for GVHD. Finally, we demonstrated the long-term persistence of adoptively transferred CB-VSTs using T-cell receptor-Vβ clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.
| S-EPMC6650740 | biostudies-literature
Project description:We report a linezolid-resistant Enterococcus faecalis infection in a cord blood stem cell transplant recipient previously treated with linezolid for bloodstream infections by vancomycin-resistant enterococci. Sequencing showed a G2576U mutation in the 23S rRNA gene. Because of the important niche of linezolid in cancer treatment, linezolid-resistant E. faecalis is noteworthy.
| S-EPMC387622 | biostudies-literature
Project description:IntroductionCytomegalovirus (CMV) can cause significant morbidity and mortality in cord blood transplant (CBT) recipients. Development of CMV-specific cell-mediated immunity (CMV-CMI) has been associated with protection against CMV clinically significant reactivation (CsCMV). In this study, we evaluated CMV-CMI reconstitution during letermovir prophylactic therapy, which prevents CsCMV without complete suppression of CMV reactivation.MethodsWe measured CMV-CMI in CMV-seropositive CBT recipients pre-transplant after Day+90 of letermovir prophylaxis and at Days +180, and +360- post-transplant using a dual color CMV-specific IFNγ/IL2 FLUOROSpot. CsCMV and nonCsCMV reactivations were abstracted from medical records. CsCMV was defined as CMV viral load ≥5,000 IU/ml using a whole blood assay.ResultsAmong 70 CBT recipients, 31 developed CMV-CMI by Day+90 and an additional eight and five participants by Days +180 and +360, respectively. Thirty-eight participants developed CMV reactivation, including nine with CsCMV. Most reactivations (33 of 38) occurred before Day+180. Early CMV-CMI was present in six out of nine participants with CsCMV, indicating a lack of protection against CsCMV. Moreover, the magnitude of CMV-CMI at Day+90 did not differ between participants with CsCMV and nonCsCMV.ConclusionApproximately 50% of CBT recipients reconstituted CMV-CMI during letermovir prophylactic therapy. However, CMV-CMI did not reach levels protective against CsCMV. Extension of CMV prophylaxis beyond Day+90 may be considered in CMV-seropositive CBT recipients.
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Project description:Cell therapies are an emerging focus for neonatal research, with benefits documented for neonatal respiratory, neurological, and cardiac conditions in pre-clinical studies. Umbilical cord blood (UCB) and umbilical cord (UC) tissue-derived cell therapy is particularly appealing for preventative or regenerative treatment of neonatal morbidities; they are a resource that can be collected at birth and used as an autologous or allogeneic therapy. Moreover, UCB contains a diverse mix of stem and progenitor cells that demonstrate paracrine actions to mitigate damaging inflammatory, immune, oxidative stress, and cell death pathways in several organ systems. In the past decade, published results from early-phase clinical studies have explored the use of these cells as a therapeutic intervention in neonates. We present a systematic review of published and registered clinical trials of UCB and cord tissue-derived cell therapies for neonatal morbidities. This search yielded 12 completed clinical studies: 7 were open-label phase I and II safety and feasibility trials, 3 were open-label dose-escalation trials, 1 was a open-label placebo-controlled trial, and 1 was a phase II randomized controlled trial. Participants totaled 206 infants worldwide; 123 (60%) were full-term infants and 83 (40%) were preterm. A majority (64.5%) received cells via an intravenous route; however, 54 (26.2%) received cells via intratracheal administration, 10 (4.8%) intraoperative cardiac injection, and 9 (4.3%) by direct intraventricular (brain) injection. Assessment of efficacy to date is limited given completed studies have principally been phase I and II safety studies. A further 24 trials investigating UCB and UC-derived cell therapies in neonates are currently registered.
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Project description:Spinal cord injury (SCI) leads to chronic and multifaceted disability, which severely impacts the physical and mental health as well as the socio-economic status of affected individuals. Permanent disabilities following SCI result from the failure of injured neurons to regenerate and rebuild functional connections with their original targets. Inhibitory factors present in the SCI microenvironment and the poor intrinsic regenerative capacity of adult spinal cord neurons are obstacles for regeneration and functional recovery. Considerable progress has been made in recent years in developing cell and molecular approaches to enable the regeneration of damaged spinal cord tissue. In this review, we highlight several potent cell-based approaches and genetic manipulation strategies (gene therapy) that are being investigated to reconstruct damaged or lost spinal neural circuits and explore emerging novel combinatorial approaches for enhancing recovery from SCI.
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Project description:Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.
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