Umbilical cord blood: an undervalued and underutilized resource in allogeneic hematopoietic stem cell transplant and novel cell therapy applications.

PURPOSE OF REVIEW: The purpose of this review is to primarily discuss the unwarranted decline in the use of umbilical cord blood (UCB) as a source of donor hematopoietic stem cells (HSC) for hematopoietic cell transplantation (HCT) and the resulting important implications in addressing healthcare inequities, and secondly to highlight the incredible potential of UCB and related birthing tissues for the development of a broad range of therapies to treat human disease including but not limited to oncology, neurologic, cardiac, orthopedic and immunologic conditions. RECENT FINDINGS: When current best practices are followed, unrelated donor umbilical cord blood transplant (CBT) can provide superior quality of life-related survival compared to other allogeneic HSC donor sources (sibling, matched or mismatched unrelated, and haploidentical) through decreased risks of relapse and chronic graft vs. host disease. Current best practices include improved UCB donor selection criteria with consideration of higher resolution human leukocyte antigen (HLA) typing and CD34+ cell dose, availability of newer myeloablative but reduced toxicity conditioning regimens, and rigorous supportive care in the early posttransplant period with monitoring for known complications, especially related to viral and other infections that may require intervention. Emerging best practice may include the use of ex vivo expanded single-unit CBT rather than double-unit CBT (dCBT) or 'haplo-cord' transplant, and the incorporation of posttransplant cyclophosphamide as with haploidentical transplant and/or incorporation of novel posttransplant therapies to reduce the risk of relapse, such as NK cell adoptive transfer. Novel, non-HCT uses of UCB and birthing tissue include the production of UCB-derived immune effector cell therapies such as unmodified NK cells, chimeric antigen receptor-natural killer cells and immune T-cell populations, the isolation of mesenchymal stem cells for immune modulatory treatments and derivation of induced pluripotent stem cells haplobanks for regenerative medicine development and population studies to facilitate exploration of drug development through functional genomics. SUMMARY: The potential of allogeneic UCB for HCT and novel cell-based therapies is undervalued and underutilized. The inventory of high-quality UCB units available from public cord blood banks (CBB) should be expanding rather than contracting in order to address ongoing healthcare inequities and to maintain a valuable source of cellular starting material for cell and gene therapies and regenerative medicine approaches. The expertise in Good Manufacturing Practice-grade manufacturing provided by CBB should be supported to effectively partner with groups developing UCB for novel cell-based therapies.

Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant.

Among reported advantages of umbilical cord blood (CB) in transplantation is lower leukemia relapse probability. Underlying cellular mechanisms of graft-vs.-leukemia (GVL) are thought to include a prominent role for T cells. Cells of the CB's mother, maternal microchimerism (MMc), were recently strongly, but indirectly, implicated in this GVL benefit. We assayed MMc directly and hypothesized benefit accrues from CB maternal T cells. MMc was quantified in 51 CBs and, within memory T, naïve T, B, NK cells, and monocytes in 27 CBs. Polymorphism-specific quantitative-PCR assays targeted maternal genotypes non-shared with CBs. Overall MMc was common and often at substantial levels. It was present in 52.9% of CB and in 33.3-55.6% of tested subsets. Remarkably, MMc quantities were greater in memory T cells than other subsets (p < 0.001). Expressed as genome equivalents (gEq) per 105 total gEq tested (gEq/105), memory T cell MMc averaged 850.2 gEq/105, while other subset mean quantities were 13.8-30.1 gEq/105. After adjustment for proportionality in CB, MMc remained 6-17 times greater in memory T, and 3-9 times greater in naïve T, vs. non-T-cell subsets. Further, CB-origin MMc was detected in vivo in a patient up to 6 mo post-transplantation, including among T cells. Overall, results revealed levels and phenotypes of CB MMc with potential relevance to CB transplantation and, more broadly, to offspring health.

Advances in umbilical cord blood manipulation-from niche to bedside.

The use of umbilical cord blood (UCB) as an alternative haematopoietic cell source in lieu of bone marrow for haematopoietic reconstitution is increasingly becoming a mainstay treatment for both malignant and nonmalignant diseases, as most individuals will have at least one available, suitably HLA-matched unit of blood. The principal limitation of UCB is the low and finite number of haematopoietic stem and progenitor cells (HSPC) relative to the number found in a typical bone marrow or mobilized peripheral blood allograft, which leads to prolonged engraftment times. In an attempt to overcome this obstacle, strategies that are often based on native processes occurring in the bone marrow microenvironment or 'niche' have been developed with the goal of accelerating UCB engraftment. In broad terms, the two main approaches have been either to expand UCB HSPC ex vivo before transplantation, or to modulate HSPC functionality to increase the efficiency of HSPC homing to the bone marrow niche after transplant both of which enhance the biological activities of the engrafted HSPC. Several early phase clinical trials of these approaches have reported promising results.

Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo.

A disadvantage of umbilical cord blood transplantation (UCBT) is the delay in immune reconstitution, placing patients at increased risk for infections after transplant. Cytomegalovirus (CMV) in particular has been shown to cause significant morbidity in patients undergoing UCBT. Here, we comprehensively evaluate the development of CD4(+) and CD8(+) T-cell responses to CMV in a cohort of patients that underwent double UCBT. Our findings demonstrate conclusively that a diverse polyclonal CMV-specific T-cell response derived from the UCB graft is primed to viral antigens as early as day 42 after UCBT, but these T cells fail to achieve sufficient numbers in vivo to control CMV reactivations. This is not due to an inherent inability of UCB-derived T cells to proliferate, as these T cells underwent rapid proliferation in vitro. The TCR diversity and antigen specificity of CMV-specific T cells remained remarkably stable in the first year after transplant, suggesting that later control of virus replication results from improved function of T cells primed early after transplant and not from de novo responses derived from later thymic emigrants. Ex vivo expansion and adoptive transfer of CMV-specific T cells isolated from UCBT recipients early after transplant could augment immunity to CMV.