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Advances in cord blood expansion technologies

cord blood expansion technologies

Umbilical cord blood stem cell transfusions are currently being used in place of bone marrow transplants1 for many life threatening conditions such as blood cancers (e.g. leukaemia), immune system and metabolic disorders.

Today, more than 40,000 cord blood transplantations2 have been performed worldwide in the treatment of over 80 conditions – up from 33 conditions less than 10 years ago3.

Ongoing advancements in stem cell research signal an exciting future for the use of cord blood stem cells. One particularly promising development is the field of cord blood expansion.

Cord blood expansion research has focused on the ability to expand the number of cells derived from a cord blood collection. An expanded cord blood unit can further boost utility in both current and future medical uses4; i.e., both in transplantation, and in regenerative medicine.

Important benefits of cell expansion include:

  •  Increasing the potential number of therapies from a single cord blood collection
  •  Providing a store of stem cells for cancer treatments throughout a child’s life
  •  Extending the timeframe over which cord blood stem cells may be used (treatments for adults require more stem cells than that required for a child)
     

Today, cord blood stem cell expansion technologies have developed significantly to suggest it is now a matter of when, not if, expanded cord blood cells will be approved for clinical use.

EXPANDED CORD BLOOD CELLS IN TRANSPLANTATION

There are currently two approaches to cord blood expansion under investigation:

  1. Using HLA matched* (or partially matched) units; and
  2. Expanding unmatched donor samples to transplant concurrently with a standard (un-expanded) matched unit
 
*Stem cell matching is based on human leukocyte antigen (HLA) markers. Passed down from parents to their children, these markers act like cell fingerprints, letting the immune system know which cells may belong in the body and which cells are foreign to it.


Expansion using HLA matched (or partially matched) units

Expansion of individual cord blood units that require HLA matching in their application is currently under investigation in Phase I and Phase II trials by Gamida Cell and Excellthera.

  • Gamida Cell is using a small molecule (Nicotinamide) to expand blood-forming stem and progenitor cells from umbilical cord blood. A 3-week culture of cord blood stem cells and Nicotinamide (together with cytokines) results in a 400-fold increase in cellularity and an average 80-fold increase in cord blood stem cells5,6.
     
  • Excellthera is utilising a small molecule UM171 as the basis for its technology. In culture, UM171 has been shown to expand stem cells about 100-fold7.
     

Both Excellthera and Gamida Cell are targeting a larger haematopoietic stem cell (HSC) expansion rate than currently obtained so they may manufacture a cryopreserved product able to overcome HLA-matching barriers and have a readily available product (avoiding the costs/time associated with the logistics of real-time expansion).

Expansion using unmatched expanded cord blood units (to augment a matched donor sample)

Nohla Therapeutics, in conjunction with the Fred Hutchinson Cancer Research Centre, has demonstrated that infusion of a non-HLA-matched expanded cord blood unit to augment a matched un-manipulated (not expanded) cord blood unit in transplant led to more rapid neutrophil and platelet recovery compared with its historical control group. This overcomes the limitation of the lower cell dose traditionally associated with a single unit cord blood transplant.

Importantly, no transplant related mortality was observed among the 15 patients in this study – leading to an excellent Disease Free Survival rate of 86% (at median follow-up of 5 years). No acute Graft versus Host Disease (GvHD) was observed even with the infusion of a non-HLA-matched expanded cell product.

Nohla has engaged in a randomised Phase II trial in which patients will receive a non-HLA matched cryopreserved expanded Cord Blood product in addition to their matched, un-manipulated cord blood transplant (NCT01690520, FHCRC Protocol 2603).The advantage of Nohla’s approach is the immediate availability of the expanded product and the relatively lower cost associated with procuring unmatched unit.

EXPANDED CORD BLOOD CELLS FOR REGENERATIVE MEDICINE

In addition to the therapeutic potential in transplant, many studies are demonstrating that cord blood contains cells that may support regeneration and/or survival of non- hematopoietic cells, such as neural, cardiac, mesenchymal, and muscle cells. Such plasticity, and the potential to produce non-hematopoietic cells at the clinical scale, could bring new alternatives in regenerative medicine treatments.

The impact of this is anticipated to magnify when using cord blood stem cell expansion technology.

This will provide the potential impact of a higher cell dose, and indeed, the potential to leverage multiple doses. Hence, the ex vivo expansion of cord-derived HSPCs is expected to have a positive impact in regenerative medicine where there is a growing range of research and clinical trials evaluating how cord blood cells may contribute to new therapies for a broad number of conditions; e.g., cerebral palsy, type-1 diabetes, spinal cord injury, autism, hearing loss and stroke.

Pioneering studies with cord blood-derived stem cells have shown promise following the observation that they can assist in salvaging damaged tissues. Application of cord blood, rich in endothelial stem and progenitor cells, can promote local blood perfusion and produce neurotrophic, angiogenic, and anti-inflammatory effects beyond the ability of other cell types.

In regenerative medicine applications for cerebral palsy and autism, Prof. Kurtzberg and colleagues at Duke University, North Carolina, observed a direct relation between the cell dose applied and the degree of favourable outcome – underlining that cell dose in this scenario is a driver of the therapeutic potential. It can be reasonably hypothesised that Prof. Kurtzberg’s observation in CP will hold in other regenerative medicine opportunities.

Using cord blood expansion technology, Cell Care, together with Monash University and the Hudson Institute of Medical Research are working to explore the potential of multiple doses with higher cell numbers in neurological conditions. Establishment of manufacturing protocols together with the initiation of randomised, controlled and double blinded studies is warranted to fully understand the enormous potential of Cord blood expansion in this area.

SUMMARY

Cord blood is recognised as a valid source for stem cell transplantation for a variety of indications including malignant and non-malignant diseases. Use today, however, can be limited by the issue of the available cell dose from cord blood volumes.

Using expansion technologies to increase the number of cells available from a cord blood unit will enhance cord blood’s application not only in regular haematopoietic transplantation but also in regenerative medicine where higher dose and multiple dose therapies may be designed from a single unit.


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1. Umbilical cord blood banking: an update. Merlin G. Butler and Jay E. Menitove. J Assist Reprod Genet (2011) 28:669-676 2. Update on umbilical cord blood transplantation, Ballen K, (2017) https://www.ncbi.nlm.nih.gov/pubmed/28928957 3. Bioinformant Industry report: Capitalising on opportunities in cord blood industry growth, www.Bioinformant.com, March 2013  4. Tiwari  A, Moeneclaey G, Jenkin G, Kirkland MA.; Exploring Life Saving Potential of Umbilical Cord Blood Derived Hematopoietic Stem  Cells; Insights in Stem Cells 2016  5. Peled T, Shoham H, Aschengrau D, Yackoubov D, Frei G, Rosenheimer G N, Lerrer B, Cohen HY, Nagler A, Fibach E, Peled A.; Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment.; Exp Hematol. 2012 Apr;40(4):342-55.e1.Horwitz ME, Chao NJ, Rizzieri DA, Long GD, Sullivan KM, Gasparetto C, Chute JP, Morris A, McDonald C, Waters-Pick B, Stiff P, Wease S, Peled A, Snyder D, Cohen EG, Shoham H, Landau E, Friend E, Peleg I, Aschengrau D, Yackoubov D, Kurtzberg J, Peled T.; Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.; J Clin Invest. 2014 Jul;124(7):3121-8. 6. Fares I, Rivest-Khan L, Cohen  S, Sauvageau  G.; Small molecule regulation of normal and leukemic stem cells.; Curr Opin Hematol. 2015 Jul;22(4):309-16    7.  Fares  I, Chagraoui  J, Gareau Y, Gingras  S, Ruel  R, Mayotte  N, Csaszar  E, Knapp  DJ,  Miller  P,  Ngom  M, Imren  S, Roy  DC,  Watts  KL,  Kiem  HP,  Herrington  R, Iscove  NN,  Humphries  RK,  Eaves  CJ, Cohen S, Marinier A, Zandstra PW, Sauvageau G.; Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal.; Science. 2014 Sep 19;345(6203):1509-12. doi: 10.1126/science.1256337.