Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.

Abstract

Background

Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.

Methods

In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.

Results

No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.

Conclusion

UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.

Trial registration

Clinicaltrials.gov NCT01221857.

Funding

Gamida Cell Ltd.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1172/jci74556

Publication Info

Horwitz, Mitchell E, Nelson J Chao, David A Rizzieri, Gwynn D Long, Keith M Sullivan, Cristina Gasparetto, John P Chute, Ashley Morris, et al. (2014). Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. The Journal of clinical investigation, 124(7). pp. 3121–3128. 10.1172/jci74556 Retrieved from https://hdl.handle.net/10161/24705.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Horwitz

Mitchell Eric Horwitz

Professor of Medicine

Allogeneic stem cell transplantation with a focus on the use of umbilical cord blood grafts; Allogenic stem cell transplantation for Sickle Cell Disease; Prevention of acute and chronic graft versus host disease; Improving immune recovery following alternative donor stem cell transplantation using donor graft manipulation.

Chao

Nelson Jen An Chao

Donald D. and Elizabeth G. Cooke Cancer Distinguished Research Professor

My research interests are in two broad areas, clinical hematopoietic stem cell and cord blood transplantation and in the laboratory studies related to graft vs. host disease and immune reconstitution. On the clinical side we are currently conducting approximately 50 different clinical protocols ranging from preparatory regimens, supportive care studies and disease specific protocols. Most of these clinical studies are centered around studies of the sources of stem cells and the methods to improve the long term outcome. There are exploratory protocols for novel therapies such as dendritic cell therapy for several malignancies, antiangiogenesis therapy, graft engineering to prevent graft-versus-host disease and antigen specific T cells or non specific NK cells to prevent relapse. Moreover a strong focus of the program is to develop cord-blood transplantation for adult patients with hematologic malignancies. The laboratory studies center on understanding the immunological events that occur with graft-vs-host disease and methods to prevent this disease. The current efforts focus on understanding murine reconstitution following transplantation, use of a peptide polymer to block MHC class II recognition of minor histocompatibility antigens, use of T cell engineering to prevent graft-versus-host disease at the same time preserving a graft-versus-malignancy effect.

For more information see http://ed-media.mc.duke.edu/BMT.nsf

Long

Gwynn Douglas Long

Professor of Medicine

1. High dose therapy and autologous and allogeneic stem cell rescue for hematologic malignancies (especially multiple myeloma) and solid tumors.
2. Non-myeloablative allogeneic transplants for hematologic malignancies and solid tumors.
3. Supportive care for hematopoietic stem cell transplants.
4. Prevention and therapy of graft versus host disease.

Sullivan

Keith Michael Sullivan

James B. Wyngaarden Distinguished Professor Emeritus of Medicine

Research areas

  • Late effects of cancer treatment and stem cell transplantation 
  • Chronic graft-versus-host disease 
  • Transplantation for sickle cell and autoimmune diseases 
  • Knowledge engineering
Overview
Early on, Dr. Sullivan and the team at Fred Hutchinson Cancer Research Center developed a systematic investigative approach for the diagnosis and treatment of chronic graft-versus-host disease (GVHD), the major cause of late morbidity and non-relapse mortality following allogeneic stem cell transplantation (SCT). As a result of this work, it became clear that blood and marrow transplant recipients require systematic long-term follow-up to evaluate and treat late complications of high-dose chemoradiotherapy and SCT.

The program grew into a large multidisciplinary team, resulting in improvement in patient outcome and quality of life. Through the late events project, he also contributed to outcomes research, computer decision support systems, and knowledge engineering for follow-up care. With quality of life as a focus, research pursued the application of SCT to diseases with high morbidity but little immediate mortality. For young patients with advanced, symptomatic sickle cell disease, myeloablative conditioning and SCT from an HLA-identical sibling has led to an 86% long-term survival free of sickle cell disease. For individuals with autoimmune diseases such as multiple sclerosis, scleroderma, and systemic lupus erythematosus, current therapy is often incomplete and significant morbidity from the disease or its treatment is observed.

Recent preclinical and clinical data suggest that high-dose immunosupression and SCT can halt the progression and, in some settings, reverse the course of autoimmune diseases. Since his arrival at Duke University, over 30 centers nationwide are participating in Duke-led phase II and III trials to test the toxicity, efficacy, and quality of life following autologous and allogeneic stem cell transplantation for autoimmune diseases.

These trials will also serve as platforms to study the immune repertoire and mechanistic pathways before and after SCT to gain greater insight into the basic mechanisms of autoimmunity.

A national repository of tissue and cell specimens is also part of these NIH-supported trials to further promote scientific study from these unique patients.

Gasparetto

Cristina Gasparetto

Professor of Medicine

Dr. Gasparetto performs both laboratory and clinical research in the field of multiple myeloma. Her primary research interests are in developing immunotherapy approaches to treating multiple myeloma particularly in conjunction with hematopoietic stem cell transplantation. Ongoing laboratory research projects include the development of dendritic cell vaccines and antibody therapies. Clinical studies include a recently approved trial involving vaccination with autologous dendritic cells pulsed with idiotypic protein following high dose chemotherapy and autologous peripheral blood stem cells transplant. Upcoming trials include novel antibody therapies for multiple myeloma. Dr. Gasparetto is also an investigator on several other clinical trials for myeloma including non-myeloablative allogeneic transplantation, high dose sequential chemotherapy and autologous peripheral blood stem cell transplantation and transplantation of partially HLA matched unrelated cord blood.


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