Methods of ex vivo expansion of human cord blood cells: challenges, successes and clinical implications

ABSTRACT

More than 40,000 unrelated cord blood transplantations (UCBT) have been performed worldwide as treatment for patients with malignant or non-malignant life threatening hematologic disorders. However, low absolute numbers of hematopoietic stem and progenitor cells (HSPCs) within a single cord blood unit has remained a limiting factor for this transplantation modality, particularly in adult recipients. Further, because UCB contains low numbers of mostly naïve T cells, immune recovery after UCBT is slow, predisposing patients to severe infections. Other causes of UCBT failure has included graft-versus-host disease (GVHD) and relapse of the underlying disease. In this article, we first review the current landscape of cord blood engineering aimed at improving engraftment. This includes approaches of UCB-HSPCs expansion and methods aimed at improving UCB-HSCPs homing. We then discuss recent approaches of cord blood engineering developed to prevent infection [generation of multivirus-specific cytotoxic T cells (VSTs) from UCB], relapse [transduction of UCB-T cells with tumor-specific chimeric receptor antigens (CARs)] and GVHD (expansion of regulatory T cells from UCB). Although many of these techniques of UCB engineering remain currently technically challenging and expensive, they are likely to revolutionize the field of UCBT in the next decades.

KEYWORDS:

• Umbilical cord blood
• UCB
• transplantation
• engraftment
• graft-versus-host disease
• HSPC
• expansion
• homing
• regulatory T cells
• chimeric receptor antigen
• cytotoxic T cells

Financial & competing interests disclosure

F Baron is senior research associate of the national fund for scientific research (F.R.S., FNRS), Belgium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Transplants using UCB allow comparable results than with BM or PBSC in both children and adults with hematological disease.

• UCBT in adult is limited by the low absolute numbers of TNCs and HSPCs contained in one UCB unit leading to slow engraftment and a relatively high incidence of graft failure.

• UCBT is associated with a lower incidence of acute GVHD than BMT or PBSCT.

• UCBT is associated with a lower incidence of chronic GVHD than BMT or PBSCT.

• Double UCBT allows adult patients without a sufficiently rich single UCB unit to benefit from UCBT.

• Double UCBT with 1 of the 2 units expanded ex vivo in the presence of either Notch ligand, MSCs, NAM, or SR1 is feasible and apparently safe, and seems to fasten neutrophil engraftment.

• Longer and larger studies are ongoing and will allow better determining the impact of ex vivo HSPC expansion on long-term hematopoiesis and on the incidence of primary and secondary graft failure.

• Several approaches aimed at improving UCB-HSPCs homing such as direct intra-bone injection of UCB, dmPGE2 UCB exposure or enforced UCB fucosylation are feasible and also seems to fasten engraftment.

• (Viral) infections are a frequent cause of morbidity/mortality after UCBT.

• Although feasible, generation of VSTs and CAR+T cells from UCB has remained technically challenging.

• Infusion of third party cord-blood-expanded T_reg (partially HLA-matched) is safe and seems to decrease the incidence of acute GVHD after double UCBT.

• A major challenge for these approaches of cord blood engineering will be to demonstrate their cost-effectiveness.