Fan X, Grant D, Gay F, Bari S, Quek J, Niam M, Soh M, Chan M, Koh M, Lodish H and Hwang W
Background: Ex vivo expansion of umbilical cord blood (UCB) hematopoietic stem and progenitor cells (HSPCs) could reduce transplant related mortality by enabling faster donor cell engraftment. Our previous study showed that addition of insulin-like growth factor binding protein 2 (IGFBP2) to mesenchymal stromal cells (MSCs) co-culture could expand non-selected UCB grafts that gave decreased incidence of graft-versus-host-disease (GVHD) in mice. In this study we carried out a pilot clinical trial to assess safety and feasibility of this UCB expansion protoc
Methods: Eligible patients with at least two UCB units matching on 4 out of 6 human leukocyte antigen loci were recruited for this study. Larger UCB unit that provided at least 2.5 × 107 total nucleated cells (TNCs) per kilogram of bodyweight was infused without any manipulation. The smaller unit which gave at least 1.5 × 107 TNCs/kg was expanded without CD34 selection and supported by MSC co-culture in presence of a cytokine cocktail consisting of 100 ng/mL stem cell factor and thrombopoietin, 50 ng/mL Flt-3L, and 20 ng/mL IGFBP2.
Results: Three patients were recruited and expansion resulted in increase of 3.5 ± 2.5 fold of TNCs, 17.9 ± 23.2 fold of overall CD34+ progenitors, 168.1 ± 114.0 fold of colony-forming unit granulocyte-macrophage and 556.7 ± 949.9 fold of primitive progenitors (CD34+CD38-CD90+cells). Sufficient HSPC expansion was attenuated by excessive cell loss of approximately 60.5% during harvesting and washing which unexpectedly gave suboptimal expanded graft dosage. Co-infusion of both units gave median of 6.5 × 105 CD34+ cells/kg. One patient maintained 100% engraftment from expanded unit at follow-up on 33 months with minimal GVHD or disease relapse. Multiorgan failure resulted in the demise of the other two patients at day 38 and day 57 post-transplant. The average time to neutrophil recovery was 38 days (range, 34-44 days). Variable number tandem repeat showed that two out of three patients achieved engraftment from the manipulated unit. The trial was terminated because of excessive mortality, primarily as a consequence of the toxicity of multiple conditioning regimens along with other comorbidities.
Conclusion: IGFBP-2 supplementation and MSC co-culture supported modest but long-term engraftment of donor cells with minimal GVHD symptoms.
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Journal of Microbiology and Pathology received 18 citations as per Google Scholar report
