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Perinatal Tissue as an Advanced Cellular Therapy Product


Perinatal tissue, such as umbilical cord blood, umbilical cord tissue and placental tissue, is a valuable source of cells for advanced cellular therapies. This includes mesenchymal stem/stromal cells and blood cells such as haematopoietic stem and progenitor cells (HSPC), natural killer cells and T-cells.  Whilst there are currently no approved therapies for umbilical cord tissue derived MSCs, there are clinical trials, in varying stages, for a multitude of conditions including spinal cord injury, stroke, and acute respiratory distress syndrome.

In contrast, umbilical cord blood is currently approved for use as a treatment option for more than 80 conditions, from blood-based cancers such as leukaemia, to metabolic disorders and immune system disorders 1. In addition, there are numerous clinical trials involving umbilical cord blood for conditions such as Crohn’s disease, lupus, and type 1 diabetes amongst others. To maximise their potential as an advanced cellular therapy, there is a requirement to increase the overall number of cells that can be derived from these perinatal tissues, without having a detrimental effect on their ability to function as a therapeutic.   

Here, we will focus on umbilical cord blood-HSPCs, whilst a valuable source of HSPCs for transplantation, a limitation exists in that the number within one unit is finite. This results in a cap to the dose of HSPCs that can be achieved from one unit and as such usually restricts the use of umbilical cord blood to children.

To overcome this in the clinic, double umbilical cord blood transplants are being performed, where two units are transplanted simultaneously to increase the overall dose of cells. In addition to this, methods to increase the number of HSPCs via expansion are being investigated and are being tested in clinical trials, these involve the inclusion of specific molecules in the growth media to support expansion. For any expanded umbilical cord blood product to reach the clinic and become a standard treatment option, methods for the manufacturing of a reliable final product for transplantation are essential, as well as the ability to manufacture at the required output to meet clinical demand. 

Bioreactors are a platform within which cells can be expanded. In these systems, the environment surrounding the cells can be monitored and controlled providing a more uniform environment for growth, including temperature, pH and oxygen levels. These systems are incredibly useful tools that can be utilised to produce advanced cell therapies, which will aid in improving the quality and reliability of the therapeutic 2.

In addition there may be a reduction in manufacturing costs (which will make it more likely for a therapeutic to become common clinical practice) and also the ability to scale the process to meet clinical demand be that for a personalised targeted therapy or for a broader general therapeutic. 

The image below represents a potential flow through for the manufacturing of an advanced cellular therapy from perinatal tissue. After the birth of the child, the perinatal tissue is collected by a health care professional using the provided collection kit. The blood and/or tissue is then packaged and transported to a processing facility, usually a cord blood bank which may be either public or private. Once received the processing facility will perform a primary processing step, which will be dependent on the cord blood bank’s standard operating procedures.

The product may then be frozen via cryopreservation to preserve the perinatal tissue until required. Whether cryopreservation is utilised or not, it is likely a secondary processing step will then be performed to purify or isolate the specific cells of interest from the other cells contained within the blood or tissue. 

The next step may then be what is known as a seed train, in this step isolated cells are expanded to increase their number for subsequent expansion in a bioreactor. During the operation of the bioreactor, critical process parameters, which have been determined through research, will be set, and maintained, providing a consistent environment for cell expansion, and real time monitoring of the process conditions provides a level of quality control that is not present when using other systems, such as culture flasks. 

Once the cells have reached the desired number, as defined by the final product requirements, or after a set period of time, they will be harvested from the bioreactor and undergo final cell processing. During this stage, the cells will be formulated for their final use and quality control checked to ensure they meet specification. The final product may be distributed to the hospital immediately for use or could undergo cryopreservation for use at a later date. 

At Biovault, in collaboration with University College London, we have been working towards the development of a stirred tank bioreactor-based expansion strategy for umbilical cord blood-HSPCs. As part of this we have transitioned from a simple static expansion to a shaken system and into a stirred tank bioreactor. The shaken system demonstrated significant improvement for the expansion of umbilical cord blood-HSPCs compared to the static system, resulting in an average 4 times more total nucleated cells and, importantly, 8 times more stem cells compared to the static system. In addition, we have also demonstrated improved growth in a stirred tank bioreactor achieving 8 times more nucleated cells and 10 times more stem cells than the static system.

This data is currently preliminary, and we are continuing to optimise the process for the stirred tank bioreactor to further enhance the expansion capability and uniformity of the final product. In addition to umbilical cord blood-HSPCs we are also making progress towards developing platforms for the manufacturing of advanced cellular therapies from other perinatal tissues, including umbilical cord tissue mesenchymal stem/stromal cells. 

References: 

  1. Verter F., et al. Diseases treated. Parents Guide to Cord Blood Foundation,2018.
  2. Eaker S., et al. Bioreactors for cell therapies: Current status and future advances. Cytotherapy, 2017: 19(1): 9-18. 


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Our hope is that the information in this brochure will empower you as you weigh-up your cord blood and tissue storage options and prepare for your family’s healthy future.